Thiazolyl- or thiadiazolyl-substituted pyridyl compounds useful as kinase inhibitors

ABSTRACT

Compounds having the following formula: 
     
       
         
         
             
             
         
       
     
     or an enantiomer, diastereomer or a pharmaceutically-acceptable salt thereof, wherein X is N or C—R 7 , are useful as kinase modulators, including IRAK-4 modulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/371,463, filed Jul. 10, 2014, which claims priority tonational phase application under 35 U.S.C. § 371 of International PatentApplication No. PCT/US2013/021134, filed Jan. 11, 2013, which claimspriority to provisional application U.S. 61/586,148, filed Jan. 13,2012, the contents of which are herein incorporated by reference.

FIELD OF THE INVENTION

This invention relates to compounds useful as kinase inhibitors,including the modulation of IRAK-4. Provided herein areheterocyclic-substituted pyridyl compounds, compositions comprising suchcompounds, and methods of their use. The invention further pertains topharmaceutical compositions containing at least one compound accordingto the invention that are useful for the treatment of conditions relatedto kinase modulation and methods of inhibiting the activity of kinases,including IRAK-4 in a mammal.

BACKGROUND OF THE INVENTION

Toll/IL-1 receptor family members are important regulators ofinflammation and host resistance. The Toll like receptor (TLR) familyrecognizes molecular patterns derived from infectious organismsincluding bacteria, fungi, parasites, and viruses (reviewed in Kawai,T., et al. 2010, Nature Immunol. 11:373-384). Ligand binding to thereceptor induces dimerization and recruitment of adaptor molecules to aconserved cytoplasmic motif in the receptor termed the Toll/IL-1receptor (TIR) domain. With the exception of TLR3, all TLRs recruit theadaptor molecule MyD88. The IL-1 receptor family also contains acytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewedin Sims, J. E., et al. 2010, Nature Rev. Immunol. 10: 89-102).

Members of the IRAK family of serine/threonine kinases are recruited tothe receptor via interactions with MyD88. The family consists of fourmembers. Several lines of evidence indicate that IRAK4 plays a criticaland non-redundant role in initiating signaling via MyD88 dependent TLRsand IL-1R family members. Structural data confirms that IRAK4 directlyinteracts with MyD88 and subsequently recruits either IRAK1 or IRAK2 tothe receptor complex to facilitate downstream signaling (Lin, S., etal., 2010, Nature 465: 885-890). IRAK4 directly phosphorylates IRAK1 tofacilitate downstream signaling to the E3 ubiquitin ligase TRAF6,resulting in activation of the serine/threonine kinase TAK1 withsubsequent activation of the NF kappaB pathway and MAPK cascade(Flannery, S. et al., 2010, Biochem. Pharmacol. 80: 1981-1991). A subsetof human patients was identified who lack IRAK4 expression (Picard, C.et al., 2003, Science 299: 2076-2079). Cells from these patients fail torespond to all TLR agonists with the exception of TLR3 as well as tomembers of the IL-1 family including IL-1β and IL-18 (Ku, C. et al.,2007, J. Exp. Med. 204: 2407-2422). Deletion of IRAK4 in mice results ina severe block in IL-1, IL-18 and all TLR dependent responses with theexception of TLR3 (Suzuki, N. et al., 2002, Nature 416: 750-754). Incontrast, deletion of either IRAK1 (Thomas, J. A. et al. 1999, J.Immunol. 163: 978-984; Swantek, J. L. et al., 2000, J. Immunol. 164:4301-4306) or IRAK2 (Wan, Y. et al., 2009, J. Biol. Chem. 284:10367-10375) results in partial loss of signaling. Furthermore, IRAK4 isthe only member of the IRAK family whose kinase activity has been shownto be required for initiation of signaling. Replacement of wild typeIRAK4 in the mouse genome with a kinase inactive mutant (KDKI) impairssignaling via all MyD88 dependent receptors including IL-1, IL-18 andall TLRs with the exception of TLR3 (Koziczak-Holbro, M. et al., 2007,J. Biol. Chem. 282: 13552-13560; Kawagoe, T et al., 2007, J. Exp. Med.204: 1013-1024; and Fraczek, J. et al., 2008, J. Biol. Chem. 283:31697-31705).

As compared to wild type animals, IRAK4 KDKI mice show greatly reduceddisease severity in mouse models of multiple sclerosis (Staschke, K. A.et al., 2009, J. Immunol. 183: 568-577), rheumatoid arthritis(Koziczak-Holbro, M. et al., 2009, Arthritis Rheum. 60: 1661-1671),atherosclerosis(Kim, T. W. et al., 2011, J. Immunol. 186: 2871-2880 andRekhter, M. et al., 2008, Bioch. Bioph. Res. Comm. 367: 642-648), andmyocardial infarction (Maekawa, Y., et al., 2009 Circulation 120:1401-1414). As described, IRAK4 inhibitors will block all MyD88dependent signaling. MyD88 dependent TLRs have been shown to contributeto the pathogenesis of multiple sclerosis, rheumatoid arthritis,cardiovascular disease, metabolic syndrome, sepsis, systemic lupuserythematosus, inflammatory bowel diseases including Crohn's disease andUlcerative colitis, autoimmune uveitis, asthma, allergy, type Idiabetes, and allograft rejection (Keogh, B. et al., 2011, TrendsPharmacol. Sci. 32: 435-442; Mann, D. L. 2011, Circ. Res. 108:1133-1145; Horton, C. G. et al., 2010, Med. Inflamm. Pii. 498980;Goldstein, D. R. et al., 2005, J. Heart Lung Transpl. 24: 1721-1729; andCario, E., 2010, Inflamm. Bowel Dis. 16: 1583-1597). Oncogenicallyactive MyD88 mutations in diffuse large B cell lymphomas have beenidentified that are sensitive to IRAK4 inhibition (Ngo, V N et al.,2011, Nature 470: 115-121). Whole genome sequencing also identifiedmutations in MyD88 associated with chronic lymphatic leukemia suggestingthat IRAK4 inhibitors may also have utility in treating leukemias(Puente, X. S. et al., 2011, Nature 475: 101-105).

In addition to blocking TLR signaling, IRAK4 inhibitors will also blocksignaling by members of the IL-1 family. Neutralization of IL-1 has beenshown to be efficacious in multiple diseases including gout; goutyarthritis; type 2 diabetes; autoinflammatory diseases including CAPS,TRAPS, FMF, adult onset stills; systemic onset juvenile idiopathicarthritis; stroke; GVHD; smoldering multiple myeloma; recurrentpericarditis; osteoarthritis; emphysema (Dinarello, C. A., 2011, Eur. J.Immunol. 41: 1203-1217 and Couillin, I. et al., 2009. J. Immunol. 183:8195-8202). In a mouse model of Alzheimer's disease, blockade of IL-1receptor improved cognitive defects, attenuated tau pathology andreduced oligomeric forms of amyloid-3 (Kitazawa, M. et al., 2011, J.Immunol. 187: 6539-6549). IL-1 has also been shown to be a critical linkto adaptive immunity, driving differentiation of the TH17 effector Tcell subset (Chung, Y., Chang, S. H. et al., 2009, Immunity 30:576-587). Therefore, IRAK4 inhibitors are predicted to have efficacy inTH17 associated diseases including multiple sclerosis, psoriasis,inflammatory bowel diseases, autoimmune uveitis, and rheumatoidarthritis (Wilke, C. M., et al., 2011, Trends Immunol. 32: 603-61).

In view of the conditions that may benefit by treatment involvingmodulation of protein kinases, it is immediately apparent that newcompounds capable of modulating protein kinases such as IRAK-4 andmethods of using these compounds could provide substantial therapeuticbenefits to a wide variety of patients.

The present invention relates to a new class of heterocyclic-substitutedpyridyl compounds found to be effective inhibitors of protein kinasesincluding IRAK-4.

SUMMARY OF THE INVENTION

Modulators of kinase activity which may generally be described asheterocyclic-substituted pyridyl compounds found are provided herein.

The invention is directed to compounds of Formula I that which areuseful as inhibitors of IRAK-4, and are useful for the treatment ofproliferative diseases, allergic diseases, autoimmune diseases andinflammatory diseases, or stereoisomers, tautomers, pharmaceuticallyacceptable slats, solvates or prodrugs thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for inhibition of IRAK-4comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

A preferred embodiment is a method for treating inflammatory andautoimmune diseases wherein the treatment of inflammatory diseases iseven more preferred. Particular, inflammatory and autoimmune diseasesinclude, but are not limited to, Crohn's, ulcerative colitis, asthma,graft versus host disease, allograft rejection, chronic obstructivepulmonary disease; Graves' disease, rheumatoid arthritis, systemic lupuserythematosis, psoriasis; CAPS, TRAPS, FMF, adult onset stills, systemiconset juvenile idiopathic arthritis, multiple sclerosis, neuropathicpain, gout, and gouty arthritis.

An alternate preferred embodiment is a method for treating metabolicdiseases, including type 2 diabetes and atherosclerosis.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment of cancers.

These and other features of the invention will be set forth in theexpanded form as the disclosure continues.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

Provided herein is at least one chemical entity chosen from compounds offormula (I):

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein

X is N or C—R⁷;

R is R¹, halogen, cyano, nitro, —O—R¹, —C(═O)—R¹, —C(═O)O—R¹,—C(═O)NR¹¹—R¹, —S(═O)₂—R¹, —NR¹¹C(═O)—R¹, —NR¹¹C(═O)NR¹¹—R¹,—NR¹¹C(═O)O—R¹, —NR¹¹S(═O)₂—R¹, or —NR¹¹—R¹;

R¹ is C₁₋₆ alkyl substituted with 0-4 R^(1a), C₁₋₆ haloalkyl, C₂₋₆alkenyl substituted with 0-3 R^(1a), C₂₋₆ alkynyl substituted with 0-3R^(1a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(1a), C₆₋₁₀ arylsubstituted with 0-3 R^(1a), a 5-10 membered heterocycle containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(1a), a5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O,and S, substituted with 0-3 R^(1a);

R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-3 R^(a), or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(a);

R² is C₆₋₁₀ aryl substituted with 0-4 R^(2a), a 5-10 memberedheterocycle containing 1-4 heteroatoms selected from N, O, and S,substituted with 0-4 R^(2a), a 5-10 membered heteroaryl containing 1-4heteroatoms selected from N, O, and S, substituted with 0-4 R^(2a);

R^(2a) at each occurrence is independently selected from hydrogen, ═O,halo, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),—(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle orheteroaryl, each comprising carbon atoms and 1-4 heteroatoms selectedfrom N, O, and S(O)_(p) substituted with 0-2 R^(a);

R³ is C₁₋₆ alkyl substituted with 0-3 R^(3a), C₁₋₆ haloalkyl, C₂₋₆alkenyl substituted with 0-3 R^(3a), C₂₋₆ alkynyl substituted with 0-3R^(3a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(3a), C₆₋₁₀ arylsubstituted with 0-3 R^(3a), a 5-10 membered heterocycle containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(3a), or a5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O,and S, substituted with 0-3 R^(3a);

R^(3a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a), or—(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p)substituted with 0-1 R^(a);

R⁴ and R⁵ are independently selected from hydrogen, C₁₋₄ alkylsubstituted with 0-1 R^(f), (CH₂)-phenyl substituted with 0-3 R^(d), anda —(CH₂)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p);

R⁶ and R⁷ are independently at each occurrence is selected fromhydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-3 R^(a), or—(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p)substituted with 0-3 R^(a), provided R⁶ and R⁷ are not both hydrogen;

R¹¹ at each occurrence is independently R^(e), C₁₋₄ alkyl substitutedwith 0-1 R^(f), CH₂-phenyl substituted with 0-3 R^(d), or —(CH₂)-5-7membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) substituted with 0-3 R^(d);

alternatively, R¹¹ and along with another R¹¹, R¹, or R² on the samenitrogen atom may join to form an optionally substituted azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, or 4-(C₁₋₆ alkyl)piperazinyl;

R^(a) is R^(d), F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-1 R^(f), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle, or —(CH₂)_(r)-5-7 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p); alternatively two R^(a) on adjacent or the same carbonatom form a cyclic acetal of the formula —O—(CH₂)_(n)—O—, or —O—CF₂—O—,wherein n is selected from 1 or 2;

R^(b) is R^(e), C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or (CH₂)_(r)-phenylsubstituted with 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl, or(CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),—(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or(CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(e) is selected from hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is hydrogen, halo, NH₂, OH, or O(C₁₋₆alkyl);

p is 0, 1, or 2;

r is 0, 1, 2, 3, or 4; and

m is 0, 1, or 2.

In another embodiment, there is provided a compound of formula I, or astereoisomer or pharmaceutically-acceptable salt thereof, wherein R² isphenyl, pyridyl, pyrimidinyl, naphthyl, benzothiazolyl,pyrazolopyridinyl, benzoisothiazolyl, triazolopyridinyl,imidazopyridinyl, benzooxazolyl, triazolopyridinyl, imidazopyridinyl,pyridopyrazinyl, quinazolinyl, pyridopyrazinyl, benzooxadiazolyl,benzothiadiazolyl, benzoimidazolyl, triazolopyridinyl,imdazopyridazinyl, pyridopyrazinyl, naphthyridinyl, quinoxalinyl,phthalazinyl, quinolinyl, indolyl, benzothiazolyl, benzodioxolyl,benzothienyl, isoquinolinyl, benzopyranyl, indolizinyl, benzofuranyl,chromonyl, coumarinyl, benzopyranyl, cinnolinyl, pyrrolopyridyl,furopyridyl, isoindolyl, or quinazolinyl, each group substituted by 1-4groups selected from R^(2a).

In another embodiment, there is provided a compound of formula I,wherein m is 0.

In another embodiment, there is provided a compound of formula I,wherein both R⁴ and R⁵ are hydrogen.

In another embodiment, there is provided a compound of formula

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

R is —C(═O)—R¹, —C(═O)O—R¹ or —C(═O)NR¹¹—R¹;

R¹ is C₁₋₆ alkyl substituted with 0-4 R^(1a), C₁₋₆ haloalkyl, C₂₋₆alkenyl substituted with 0-3 R^(1a), C₂₋₆ alkynyl substituted with 0-3R^(1a), C₃₋₁₀ cycloalkyl substituted with 0-3 R^(1a), C₆₋₁₀ arylsubstituted with 0-3 R^(1a), a 5-10 membered heterocyclyl containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(1a), or a5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O,and S, substituted with 0-3 R^(1a);

R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-3 R^(a), or—(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p)substituted with 0-3 R^(a);

R² is phenyl, pyridyl, pyrimidinyl, naphthyl, benzothiazolyl,pyrazolopyridinyl, benzoisothiazolyl, triazolopyridinyl,imidazopyridinyl, benzooxazolyl, triazolopyridinyl, imidazopyridinyl,pyridopyrazinyl, quinazolinyl, pyridopyrazinyl, benzooxadiazolyl,benzothiadiazolyl, benzoimidazolyl, triazolopyridinyl,imdazopyridazinyl, pyridopyrazinyl, naphthyridinyl, quinoxalinyl,phthalazinyl, quinolinyl, indolyl, benzothiazolyl, benzodioxolyl,benzothienyl, isoquinolinyl, benzopyranyl, indolizinyl, benzofuranyl,chromonyl, coumarinyl, benzopyranyl, cinnolinyl, pyrrolopyridyl,furopyridyl, isoindolyl, or quinazolinyl each group substituted by 1-4groups selected from R^(2a);

R^(2a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a), or—(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p)substituted with 0-1 R^(a);

R³ is C₁₋₆ alkyl substituted with 0-3 R^(3a), or a C₃₋₇cycloalkyl,phenyl, tetrahydropyranyl, tetrahydrofuranyl, or oxetane ring, each ringoptionally substituted with 0-3 R^(3a);

R^(3a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a), or—(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) substituted with 0-1 R^(a);

R⁷ is F, Cl, Br, OCF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(b),—NR^(e)R^(e), or —NR^(e)C(O)OR^(c) C₁₋₆ alkyl substituted with 0-2R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or(CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R¹¹ at each occurrence is independently hydrogen, C₁₋₄ alkyl substitutedwith 0-1 R^(f), CH₂-phenyl substituted with 0-3 R^(d), or —(CH₂)-5-7membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p) substituted with 0-3 R^(d);

R^(a) is hydrogen, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 memberedcarbocycle, or —(CH₂)_(r)-5-7 membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),alternatively two R^(a) on adjacent or the same carbon atom form acyclic acetal of the formula —O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n isselected from 1 or 2;

R^(b) is hydrogen, C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or(CH₂)_(r)-phenyl substituted with 0-3 R^(d);

R^(c) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),—(CH₂)_(r)C(O)R^(e), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl, or(CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(e) is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f);

R^(f) is hydrogen, F, Cl, Br, NH₂, OH, or O(C₁₋₆alkyl);

r is 0, 1, 2, 3, or 4; and

p is 0, 1, or 2.

In another embodiment, there is provided a compound of formula I, or astereoisomer or pharmaceutically acceptable salt thereof, wherein R² isselected from

each group substituted by 0-4 R^(2a).

In an even more preferred embodiment there is provided a compound offormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein R^(2a) is selected from hydrogen, ═O, C₁₋₆alkyl, F, Cl,Br, —OC1-6alkyl, pyridyl, morpholinyl, oxazolyl, C(O)O C1-6alkyl,C(O)NHC1-6alkyl, CN, C1-6haloalkyl, NH₂, —NHC₁₋₆alkyl, N(C₁₋₆alkyl), OH,and a 5-6 membered heterocycle having 1-3 ring atoms selected from O, Nor S.

In a more preferred embodiment compounds of formula I are provided, or astereoisomer or pharmaceutically acceptable salt thereof, wherein R^(2a)is independently selected from 1-4 groups at each occurrence fromfluoro, chloro, ═O, —OH, OMe, hydrogen, CO₂Et, CONHMe, CN, CF₃, NH₂, OH,CN, CONH₂, pyridyl, morpholinyl, and oxazolyl.

In yet another more preferred embodiment compounds of formula I areprovided, or a stereoisomer or pharmaceutically acceptable salt thereof,wherein R₂ is selected from:

In another embodiment, there is provided a compound of formula I, or astereoisomer or pharmaceutically acceptable salt thereof, wherein R² isselected from

In another embodiment, there is provided a compound of formula I, or astereoisomer or pharmaceutically acceptable salt thereof, wherein R² isselected from

In a further embodiment, there is provided a compound of formula I, or astereoisomer or pharmaceutically acceptable salt thereof, wherein R isselected from —C(O)NH₂, —C(O)OC₁₋₆alkyl, —C(O)NH(C₁₋₆alkyl),—C(O)N(C₁₋₆alkyl)₂,

each group substituted by 0-3 R^(1a).

In a further preferred embodiment, there is provided a compound offormula I, or a stereoisomer or pharmaceutically acceptable saltthereof, wherein

R^(1a) at each occurrence is independently selected from hydrogen, F,Cl, Br, C₁₋₆alkyl, C₁₋₆haloalkyl, —(CH₂)_(n)OH, —(CH₂)_(n)NH₂,—(CH₂)_(n)CN, C(O)NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, —NHC(O)C₁₋₆alkyl,═O, acyl, NH₂, H, NHC(O)₂C₁₋₆alkyl, OC₁₋₆alkyl, C(O)phenyl, —(CH₂)_(n)morpholinyl, —(CH₂)_(n)phenyl, —(C₂)_(n)benzodioxo,—(CH₂)_(n)pyrrolidinyl, —(CH₂)_(n)pyrimidinyl, —(CH₂)_(n)pyridyl,—(CH₂)_(n)piperidinyl, —(CH₂)_(n)diazapanyl, each group optionallyfurther substituted by 1-3 groups selected from C₁₋₆alkyl, halo,haloC₁₋₆alkyl, C₃₋₇cycloalkyl, tetrahydrofuranyl, —NH(acyl), NH₂,—NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂, —OC₁₋₆alkyl, acyl, CN, OH, piperidinyl,pyridyl, morpholinyl, pyrrolidinyl, and pyrimidinyl, wherein n isselected from 0, 1, 2, 3, and 4.

In a more preferred embodiment compounds of formula I are provided, or astereoisomer or pharmaceutically acceptable salt thereof, in whichR^(1a) is selected from the following:

In another embodiment, compounds of formula I are provided, or astereoisomer or pharmaceutically acceptable salt thereof, wherein X isCR⁷; and R⁷ is hydrogen or C₁₋₆alkyl.

In another embodiment, compounds of formula I are provided, or astereoisomer or pharmaceutically acceptable salt thereof, wherein X isN.

In yet another embodiment compounds of formula I are provided, or astereoisomer or pharmaceutically acceptable salt thereof, wherein R³ isC₁₋₆ alkyl substituted with 0-3 R^(3a) or phenyl optionally substitutedwith 0-3 R^(3a).

In another preferred embodiment, compounds of formula I are provided, ora stereoisomer or pharmaceutically acceptable salt thereof, wherein R³is selected from C₁₋₆ alkyl (R³ is preferably isopropyl).

In another embodiment, there is provided a pharmaceutical compositioncomprising one or more compounds of formula I and a pharmaceuticallyacceptable carrier or diluent.

The present invention is also directed to pharmaceutical compositionsuseful in treating diseases associated with kinase modulation, includingmodulation (especially inhibition) of IRAK-4, comprising compounds offormula (I), or pharmaceutically-acceptable salts thereof, andpharmaceutically-acceptable carriers or diluents.

The invention further relates to methods of treating diseases associatedwith the kinase modulation, including the modulation of IRAK-4,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound according to formula (I).

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases (or use of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof, forthe manufacture of a medicament for the treatment of these diseases),comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating a disease (oruse of the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, for the manufacture of a medicament for the treatment of thesediseases), comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound of formula I,wherein the disease is Crohn's, ulcerative colitis, asthma, graft versushost disease, allograft rejection, chronic obstructive pulmonarydisease; Graves' disease, rheumatoid arthritis, systemic lupuserythematosis, psoriasis; CAPS, TRAPS, FMF, adult onset stills, systemiconset juvenile idiopathic arthritis, multiple sclerosis, neuropathicpain, gout, and gouty arthritis.

The present invention also provides a method of treating a metabolicdisease (or use of the compounds of the present invention orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs thereof, for the manufacture of a medicament for thetreatment of these diseases) wherein the disease is selected from type 2diabetes and atherosclerosis.

In addition, the present invention also provides a method of treating acondition (or use of the compounds of the present invention orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs thereof, for the manufacture of a medicament for thetreatment of these conditions) comprising administering to a patient inneed of such treatment a therapeutically-effective amount of a compoundof formula I, wherein the condition is selected from acute myelogenousleukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi'ssarcoma, multiple myeloma, solid tumors, ocular neovasculization, andinfantile haemangiomas, B cell lymphoma, systemic lupus erythematosus(SLE), rheumatoid arthritis, psoriatic arthritis, multiple vasculitides,idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergicrhinitis, multiple sclerosis (MS), transplant rejection, Type Idiabetes, membranous nephritis, inflammatory bowel disease, autoimmunehemolytic anemia, autoimmune thyroiditis, cold and warm agglutinindiseases, Evan's syndrome, hemolytic uremic syndrome/thromboticthrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjögren's syndrome,peripheral neuropathies, pemphigus vulgaris and asthma.

The present invention also provides a method for treating a rheumatoidarthritis (or use of the compounds of the present invention orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs thereof, for the manufacture of a medicament for thetreatment of rheumatoid arthritis), comprising administering to apatient in need of such treatment a therapeutically-effective amount ofa compound of formula I.

The present invention also provides a method of treating a TLR/IL-1mediated disease (or use of the compounds of the present invention orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs thereof, for the manufacture of a medicament for thetreatment of these diseases), comprising administering to a patient inneed of such treatment a therapeutically-effective amount of a compoundof formula I

The present invention also provides a method of treating a TLR/IL-1mediated disease (or use of the compounds of the present invention orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs thereof, for the manufacture of a medicament for thetreatment of these diseases), comprising administering to a patient inneed of such treatment a therapeutically-effective amount of a compoundof formula I, wherein the TLR/IL-1 mediated disease is a diseasemodulated by a kinase selected from IRAK-4.

The present invention also provides a method of treating diseases,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula I, orpharmaceutically acceptable salt thereof, in combination with othertherapeutic agents.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, for use in therapy.

In another embodiment, compounds of formula I are selected fromexemplified compounds or combinations of exemplified compounds or otherembodiments herein.

In another embodiment, the present invention is directed to apharmaceutical composition comprising a compound of formula (I) and oneor more active ingredients.

In another embodiment, the present invention is directed to a method formodulation of chemokine or chemokine receptor activity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a pharmaceutical composition comprised of a compound offormula (I) and one or more active ingredients.

In another embodiment, the present invention is directed to a method formodulation of CCR-1 receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of apharmaceutical composition comprised of a compound of formula (I) andone or more active ingredients.

In another embodiment are compounds having an IC₅₀<1000 nM in the IRAK-4assay described below.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects and/orembodiments of the invention noted herein. It is understood that any andall embodiments of the present invention may be taken in conjunctionwith any other embodiment or embodiments to describe additional morepreferred embodiments. It is also to be understood that each individualelement of the preferred embodiments is its own independent preferredembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of terms used in this specification andappended claims. The initial definition provided for a group or termherein applies to that group or term throughout the specification andclaims, individually or as part of another group, unless otherwiseindicated.

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated.

When any variable (e.g., R³) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R³, then saidgroup may optionally be substituted with up to two R³ groups and R³ ateach occurrence is selected independently from the definition of R³.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these can be converted to N-oxides by treatmentwith an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, all shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

A dash “-” that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

The term “optionally substituted” in reference to a particular moiety ofthe compound of Formula I (e.g., an optionally substituted heteroarylgroup) refers to a moiety having 0, 1, 2, or more substituents. Forexample, “optionally substituted alkyl” encompasses both “alkyl” and“substituted alkyl” as defined below. It will be understood by thoseskilled in the art, with respect to any group containing one or moresubstituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,synthetically non-feasible and/or inherently unstable.

As used herein, the term “at least one chemical entity” isinterchangeable with the term “a compound.”

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁₋₁₀ alkyl”(or alkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈,C₉, and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can beunsubstituted or substituted so that one or more of its hydrogens arereplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like.

Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more doublecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkenyl” (or alkenylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkenyl groups. Examples of alkenyl include, but arenot limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl,2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more triplecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkynyl” (or alkynylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl, propynyl, butynyl,pentynyl, hexynyl and the like.

One skilled in the field will understand that, when the designation“CO₂” is used herein, this is intended to refer to the group

When the term “alkyl” is used together with another group, such as in“arylalkyl”, this conjunction defines with more specificity at least oneof the substituents that the substituted alkyl will contain. Forexample, “arylalkyl” refers to a substituted alkyl group as definedabove where at least one of the substituents is an aryl, such as benzyl.Thus, the term aryl(C₀₋₄)alkyl includes a substituted lower alkyl havingat least one aryl substituent and also includes an aryl directly bondedto another group, i.e., aryl(C₀)alkyl. The term “heteroarylalkyl” refersto a substituted alkyl group as defined above where at least one of thesubstituents is a heteroaryl.

When reference is made to a substituted alkenyl, alkynyl, alkylene,alkenylene, or alkynylene group, these groups are substituted with oneto three substituents as defined above for substituted alkyl groups.

The term “alkoxy” refers to an oxygen atom substituted by alkyl orsubstituted alkyl, as defined herein. For example, the term “alkoxy”includes the group —O—C₁₋₆alkyl such as methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, andthe like. “Lower alkoxy” refers to alkoxy groups having one to fourcarbons.

It should be understood that the selections for all groups, includingfor example, alkoxy, thioalkyl, and aminoalkyl, will be made by oneskilled in the field to provide stable compounds.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo, or keto, (i.e., ═O)then 2 hydrogens on the atom are replaced. Keto substituents are notpresent on aromatic moieties. Unless otherwise specified, substituentsare named into the core structure. For example, it is to be understoodthat when (cycloalkyl)alkyl is listed as a possible substituent, thepoint of attachment of this substituent to the core structure is in thealkyl portion. Ring double bonds, as used herein, are double bonds thatare formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds or useful syntheticintermediates. A stable compound or stable structure is meant to imply acompound that is sufficiently robust to survive isolation from areaction mixture to a useful degree of purity, and subsequentformulation into an efficacious therapeutic agent. It is preferred thatthe presently recited compounds do not contain a N-halo, S(O)₂H, orS(O)H group.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to includeC₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbomyl, and the like. As used herein, “carbocycle” or“carbocyclic residue” is intended to mean any stable 3, 4, 5, 6, or7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-memberedbicyclic or tricyclic ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridgedrings are also included in the definition of carbocycle (e.g.,[2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andphenyl. When the term “carbocycle” is used, it is intended to include“aryl”. A bridged ring occurs when one or more carbon atoms link twonon-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa bicyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6 to 12 carbon atoms in the ring portion, such as phenyl,and naphthyl groups, each of which may be substituted.

Accordingly, in compounds of formula (I), the term “cycloalkyl” includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclooctyl, etc., as well as the following ring systems,

and the like, which optionally may be substituted at any available atomsof the ring(s). Preferred cycloalkyl groups include cyclopropyl,cyclopentyl, cyclohexyl, and

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

The term “haloalkyl” means a substituted alkyl having one or more halosubstituents. For example, “haloalkyl” includes mono, bi, andtrifluoromethyl.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes OCF₃.

Thus, examples of aryl groups include:

(fluorenyl) and the like, which optionally may be substituted at anyavailable carbon or nitrogen atom. A preferred aryl group isoptionally-substituted phenyl.

The terms “heterocycloalkyl”, “heterocycle”, “heterocyclo”,“heterocyclic”, or “heterocyclyl” may be used interchangeably and referto substituted and unsubstituted non-aromatic 3- to 7-memberedmonocyclic groups, 7- to 11-membered bicyclic groups, and 10- to15-membered tricyclic groups, in which at least one of the rings has atleast one heteroatom (O, S or N), said heteroatom containing ringpreferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Eachring of such a group containing a heteroatom can contain one or twooxygen or sulfur atoms and/or from one to four nitrogen atoms providedthat the total number of heteroatoms in each ring is four or less, andfurther provided that the ring contains at least one carbon atom. Thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenatoms may optionally be quatemized. The fused rings completing thebicyclic and tricyclic groups may contain only carbon atoms and may besaturated, partially saturated, or unsaturated. The heterocyclo groupmay be attached at any available nitrogen or carbon atom. The term“heterocycle” includes “heteroaryl” groups. As valence allows, if saidfurther ring is cycloalkyl or heterocyclo it is additionally optionallysubstituted with ═O (oxo).

Exemplary monocyclic heterocyclyl groups include azetidinyl,pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl,thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl,2-oxoazepinyl, azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl,morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinylsulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like.Exemplary bicyclic heterocyclo groups include quinuclidinyl. Additionalmonocyclic heterocyclyl groups include

The term “heteroaryl” refers to substituted and unsubstituted aromatic5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups,and 11- to 14-membered tricyclic groups which have at least oneheteroatom (0, S or N) in at least one of the rings, saidheteroatom-containing ring preferably having 1, 2, or 3 heteroatomsselected from O, S, and N. Each ring of the heteroaryl group containinga heteroatom can contain one or two oxygen or sulfur atoms and/or fromone to four nitrogen atoms provided that the total number of heteroatomsin each ring is four or less and each ring has at least one carbon atom.The fused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quatemized. Heteroaryl groupswhich are bicyclic or tricyclic must include at least one fully aromaticring but the other fused ring or rings may be aromatic or non-aromatic.The heteroaryl group may be attached at any available nitrogen or carbonatom of any ring. As valence allows, if said further ring is cycloalkylor heterocyclo it is additionally optionally substituted with ═O (oxo).

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

In compounds of formula (I), preferred heteroaryl groups include

and the like, which optionally may be substituted at any availablecarbon or nitrogen atom.

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl),heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl) orheteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl,thiazolyl, and furyl) the reference is intended to include rings having0 to 3, preferably 0-2, substituents selected from those recited abovefor the aryl, cycloalkyl, heterocyclo and/or heteroaryl groups, asappropriate.

The term “carbocyclyl” or “carbocyclic” refers to a saturated orunsaturated monocyclic or bicyclic ring in which all atoms of all ringsare carbon. Thus, the term includes cycloalkyl and aryl rings.Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples ofmono- and bicyclic carbocycles include cyclopropyl, cyclobutyl,cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,phenyl and naphthyl. The carbocyclic ring may be substituted in whichcase the substituents are selected from those recited above forcycloalkyl and aryl groups.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The compounds of formula (I) may exist in a free form (with noionization) or can form salts which are also within the scope of thisinvention. Unless otherwise indicated, reference to an inventivecompound is understood to include reference to the free form and tosalts thereof. The term “salt(s)” denotes acidic and/or basic saltsformed with inorganic and/or organic acids and bases. In addition, theterm “salt(s) may include zwitterions (inner salts), e.g., when acompound of formula (I), contains both a basic moiety, such as an amineor a pyridine or imidazole ring, and an acidic moiety, such as acarboxylic acid. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, such as, for example,acceptable metal and amine salts in which the cation does not contributesignificantly to the toxicity or biological activity of the salt.However, other salts may be useful, e.g., in isolation or purificationsteps which may be employed during preparation, and thus, arecontemplated within the scope of the invention. Salts of the compoundsof the formula (I) may be formed, for example, by reacting a compound ofthe formula (I) with an amount of acid or base, such as an equivalentamount, in a medium such as one in which the salt precipitates or in anaqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts; alkaline earth metal salts such ascalcium and magnesium salts; barium, zinc, and aluminum salts; saltswith organic bases (for example, organic amines) such as trialkylaminessuch as triethylamine, procaine, dibenzylamine,N-benzyl-β-phenethylamine, 1-ephenamine, N,N′-dibenzylethylene-diamine,dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamineor similar pharmaceutically acceptable amines and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quatemized with agents such as lower alkyl halides (e.g., methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g., benzyl and phenethylbromides), and others. Preferred salts include monohydrochloride,hydrogensulfate, methanesulfonate, phosphate or nitrate salts.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, the disclosure of which is hereby incorporated by reference.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.Stereoisomers may include compounds which are optical isomers throughpossession of one or more chiral atoms, as well as compounds which areoptical isomers by virtue of limited rotation about one or more bonds(atropisomers). The definition of compounds according to the inventionembraces all the possible stereoisomers and their mixtures. It veryparticularly embraces the racemic forms and the isolated optical isomershaving the specified activity. The racemic forms can be resolved byphysical methods, such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates from the conventionalmethods, such as, for example, salt formation with an optically activeacid followed by crystallization.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Prodrugs and solvates of the inventive compounds are also contemplated.The term “prodrug” denotes a compound which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of the formula (I), and/or a salt and/orsolvate thereof. Any compound that will be converted in vivo to providethe bioactive agent (i.e., the compound for formula (I)) is a prodrugwithin the scope and spirit of the invention. For example, compoundscontaining a carboxy group can form physiologically hydrolyzable esterswhich serve as prodrugs by being hydrolyzed in the body to yield formula(I) compounds per se. Such prodrugs are preferably administered orallysince hydrolysis in many instances occurs principally under theinfluence of the digestive enzymes. Parenteral administration may beused where the ester per se is active, or in those instances wherehydrolysis occurs in the blood. Examples of physiologically hydrolyzableesters of compounds of formula (I) include C₁₋₆alkylbenzyl,4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl, pivaloyloxymethyl orpropionyloxymethyl, C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g.methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl andother well known physiologically hydrolyzable esters used, for example,in the penicillin and cephalosporin arts. Such esters may be prepared byconventional techniques known in the art.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 112, pp. 309-396, edited by K. Widder, etal. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsenand H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H.Bundgaard, pp. 113-191 (1991); and

c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, pp. 1-38(1992), each of which is incorporated herein by reference.

Compounds of the formula (I) and salts thereof may exist in theirtautomeric form, in which hydrogen atoms are transposed to other partsof the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that theall tautomeric forms, insofar as they may exist, are included within theinvention. Additionally, inventive compounds may have trans and cisisomers,

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula (I) are also with the scope of the presentinvention. Methods of solvation are generally known in the art.

Utility

The compounds of the invention modulate kinase activity, including themodulation of IRAK-4. Other types of kinase activity that may bemodulated by the compounds of the instant invention include, but are notlimited to, the Pelle/IRAK family and mutants thereof.

Accordingly, compounds of formula (I) have utility in treatingconditions associated with the modulation of kinase activity, andparticularly the selective inhibition of IRAK-4 activity or theinhibition of IRAK and other Pelle family kinases. Such conditionsinclude TLR/IL-1family receptor associated diseases in which cytokinelevels are modulated as a consequence of intracellular signaling.Moreover, the compounds of formula (I) have advantageous selectivity forIRAK-4 activity, preferably from at least 20 fold to over 1,000 foldmore selective.

As used herein, the terms “treating” or “treatment” encompass thetreatment of a disease state in a mammal, particularly in a human, andinclude: (a) preventing or delaying the occurrence of the disease statein a mammal, in particular, when such mammal is predisposed to thedisease state but has not yet been diagnosed as having it; (b)inhibiting the disease state, i.e., arresting its development; and/or(c) achieving a full or partial reduction of the symptoms or diseasestate, and/or alleviating, ameliorating, lessening, or curing thedisease or disorder and/or its symptoms.

In view of their activity as selective inhibitors IRAK-4, compounds ofFormula (I) are useful in treating TLR/IL-1 family receptor associateddiseases, but not limited to, inflammatory diseases such as Crohn's andulcerative colitis, asthma, graft versus host disease, allograftrejection, chronic obstructive pulmonary disease; autoimmune diseasessuch as Graves' disease, rheumatoid arthritis, systemic lupuserythematosis, psoriasis; autoinflammatory diseases including CAPS,TRAPS, FMF, adult onset stills, systemic onset juvenile idiopathicarthritis, gout, gouty arthritis; metabolic diseases including type 2diabetes, atherosclerosis, myocardial infarction; destructive bonedisorders such as bone resorption disease, osteoarthritis, osteoporosis,multiple myeloma-related bone disorder; proliferative disorders such asacute myelogenous leukemia, chronic myelogenous leukemia; angiogenicdisorders such as angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and Shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, cerebral ischemias orneurodegenerative disease caused by traumatic injury, oncologic andviral diseases such as metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, and HIV infection and CMV retinitis, AIDS, respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoisosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, meloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hyposia, vascular hyperplasia, cardiac and renalreperfusion injury, thrombosis, cardiac hypertrophy, thrombin-inducedplatelet aggregation, endotoxemia and/or toxic shock syndrome,conditions associated with prostaglandin endoperoxidase syndase-2, andpemphigus vulgaris. Preferred methods of treatment are those wherein thecondition is selected from Crohn's and ulcerative colitis, allograftrejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis,psoriatic arthritis, and pemphigus vulgaris. Alternatively preferredmethods of treatment are those wherein the condition is selected fromischemia reperfusion injury, including cerebral ischemia reperfusionsinjury arising from stroke and cardiac ischemia reperfusion injuryarising from myocardial infarction. Another preferred method oftreatment is one in which the condition is multiple myeloma.

In addition, the kinase inhibitors of the present invention inhibit theexpression of inducible pro-inflammatory proteins such as prostaglandinendoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2(COX-2), IL-1, IL-6, IL-18, chemokines. Accordingly, additionalIRAK-4-associated conditions include edema, analgesia, fever and pain,such as neuromuscular pain, headache, pain caused by cancer, dental painand arthritis pain. The inventive compounds also may be used to treatveterinary viral infections, such as lentivirus infections, including,but not limited to equine infectious anemia virus; or retro virusinfections, including feline immunodeficiency virus, bovineimmunodeficiency virus, and canine immunodeficiency virus.

When the terms “IRAK-4-associated condition” or “IRAK-4-associateddisease or disorder” are used herein, each is intended to encompass allof the conditions identified above as if repeated at length, as well asany other condition that is affected by IRAK-4 kinase activity.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof atherapeutically-effective amount of at least one compound of Formula (I)or a salt thereof. “Therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to inhibit IRAK-4and/or treat diseases.

The methods of treating IRAK-4 kinase-associated conditions may compriseadministering compounds of Formula (I) alone or in combination with eachother and/or other suitable therapeutic agents useful in treating suchconditions. Accordingly, “therapeutically effective amount” is alsointended to include an amount of the combination of compounds claimedthat is effective to inhibit IRAK-4 and/or treat diseases associatedwith IRAK-4.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf);cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-αinhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor,and rapamycin (sirolimus or Rapamune) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating IRAK-4kinase-associated conditions, including TLR and IL-1 family receptormediated diseases as described above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula (I) and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th ed., 1985, which is incorporated herein by reference inits entirety.

The compounds of Formula (I) may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrastemal injection orinfusion techniques (e.g., as sterile injectable aq. or non-aq.solutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agentsand stabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The therapeutically-effective amount of a compound of the presentinvention may be determined by one of ordinary skill in the art, andincludes exemplary dosage amounts for a mammal of from about 0.05 to1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats, horses, and the like. Thus, when the term “patient” is usedherein, this term is intended to include all subjects, most preferablymammalian species that are affected by mediation of IRAK-4 enzymelevels.

Biological Assays IRAK4 Inhibition Assay:

The assays were performed in U-bottom 384-well plates. The final assayvolume was 30 μL prepared from 15 μL additions of enzyme and substrates(fluoresceinated peptide and ATP) and test compounds in assay buffer (20mM HEPES pH 7.2, 10 mM MgCl₂, 0.015% Brij35 and 4 mM DTT). The reactionwas initiated by the combination of IRAK4 with substrates and testcompounds. The reaction was incubated at room temperature for 60 min.and terminated by adding 45 μL of 35 mM EDTA to each sample. Thereaction mixture was analyzed on the Caliper LabChip 3000 (Caliper,Hopkinton, Mass.) by electrophoretic separation of the fluorescentsubstrate and phosphorylated product. Inhibition data were calculated bycomparison to no enzyme control reactions for 100% inhibition andvehicle-only reactions for 0% inhibition. The final concentrations ofreagents in the assays are ATP, 500 μM; FL-IPTSPITTTYFFFKKK peptide 1.5μM; IRAK4, 0.6 nM; and DMSO, 1.6%.

IRAK4 Inhibition Data Example No. IRAK4 IC₅₀ (μM) 1 0.0253 3 0.0025 60.0028 7 0.0032 8 0.0033 19 0.0032 23 0.9607 25 0.0027 27 0.0018 310.7638 48 0.5759 56 0.795 59 0.024 81 0.026 82 0.0031 106 0.875 1080.0027 115 0.0229 128 0.0264 129 0.0254 130 0.0221 143 0.6759 148 0.5642152 0.0245 161 0.023 176 0.6158 177 0.8128

Methods of Preparation

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used. This will sometimes requirea judgment to modify the order of the synthetic steps or to select oneparticular process scheme over another in order to obtain a desiredcompound of the invention. It will also be recognized that another majorconsideration in the planning of any synthetic route in this field isthe judicious choice of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe trained practitioner is Greene and Wuts (Protective Groups InOrganic Synthesis, Third Edition, Wiley and Sons, 1999).

Triazole derivatives of general formula (I) can be prepared according tothe method outlined in Scheme 1. Displacement of the C4 chloride ofethyl 4,6-dichloronicotinate (1) with an appropriately substituted aminecan provide the C4 amino product (1.1) which can be further reacted withanother amine in the presence of a catalyst, such as Pd, or under hightemperatures to provide the bis-amino substituted pyridine (1.2).Hydrolysis of the ester with a suitable hydroxide source, such as KOH,can provide the carboxylic acid 1.3 which can be reacted with a suitablereagent, such as ethyl 2-amino-2-hydrazonoacetate, to afford theheterocycle precursor 1.4. Cyclization under thermal control can affordthe general C5 triazole shown in Scheme 1.

Additional compounds of the general formula (1) containing thiadiazolesubstitutions at position 5 of the pyridine ring can be preparedaccording to the methods outlined in Scheme 2. The reaction of compound1.1 with hydrazine at elevated temperatures in an appropriate solvent,such as ethanol, can provide compound 2.1. Further reaction with methyl2-chloro-2-oxoacetate in the presence of a base followed by cyclizationcan provide compound 2.3. Hydrolysis of the ester under standardconditions followed by amide bond formation can provide compound 2.4.Alternatively, 2.4 can be prepared directly from 2.3 by direct reactionwith an amine at elevated temperatures. Incorporation of the C2 aminefragment under metal catalyzed conditions or elevated temperatures canprovide the thiadiazole derivatives of the general formula (I).Additional functional group manipulations can be performed at variousregions of the molecule. For example, compounds of the formula 2.5 canbe reacted with a hydroxide source, such as KOH, to provide thecarboxylic acid 2.6. This can then be further reacted with a variety ofreagents, such as an amine, to provide intermediates, such as 2.7, whichcan be reacted further with amines at position 2 to afford compounds ofthe general formula (I).

Thiazole derived analogs can be prepared according to the generalmethods outlined in Scheme 3. Reaction of compound 3.1, the hydrolysisproduct of compound 1.1, can be reacted with a halogenating reagent,such as oxalyl chloride followed by quenching with an amine source, suchas ammonia, to provide intermediates of the formula 3.2. Dehydration ofthe amide can provide nitrile 3.3 which can be further reacted with anamine to provide intermediates of the formula 3.4. Conversion of thenitrile to a thioamide (3.5) followed by condensation with a halo ketonecan provide thiazole substituted compounds of the formula 3.6. Furtherhydrolysis of 3.6 can provide the acid 3.7 which, in turn can be reactedunder a variety of functional group transforming conditions, such as theconversion to an amine 3.8, to provide additional compounds of thegeneral formula I.

Similarly, oxazole compounds of the general formula I can be preparedaccording to the general procedures outlined in Scheme 4. Treatment ofcompound 3.1 with a chlorinating reagent can provide compounds such as4.1 which can then be reacted with a variety of substituted aminoketones then cyclized to the desired oxazole intermediate 4.2. Reactionat C2 with an amine using previously stated conditions can provide theintermediate 4.3. Intermediates 4.3 and 4.2 can both be manipulated toprovide compounds of the general formula I according to the methodsoutlined below. First, 4.3 can be hydrolyzed and coupled with amines toform amide analogs of formula I. Alternatively, the acid 4.4 can beconverted to the amine 4.5 under Curtius reaction conditions, and thenfurther functionalized to amide, carbamates, sulfonamides, ureas, alkyland aryl amines to name a few. Additionally, intermediate 4.2 can firstundergo hydrolysis and functional group manipulation at the oxazole asjust described then coupled with an amine at C2.

Reaction of hydrazide 5.1 with carbon disulfide followed by alkylationcan provide the intermediate 5.3. Oxidation with a reagent such asMCPBA, can provide the sulfone 5.4 which can be reacted preferentiallyat the oxadiazole to give intermediates such as 5.5. Further reactionwith an amine in the presence of a catalyst, such as Pd, or at elevatedtemperatures, can provide compounds of the general formula I.Alternatively, the reaction of 5.1 with a carboxylic acid with acoupling reagent such as HATU can provide the acyl hydrazide 5.6 whichcan be cyclized to 5.7 and further reacted on to compounds of thegeneral formula I in the presence of an amine. It is understood to oneskilled in the art that the R groups may be functionalized, for exampleas a protected amine or alcohol, in such a manner that furthermanipulations are allowable in the context of these general Schemes.Additional functional groups that can also be considered for these typesof manipulations are: nitriles, halides, esters, alkenes, alkynes andnitro groups.

Reaction of hydrazide 5.1 with a carbonylating reagent, such as CDI, canprovide compounds of the general formula 6.1. Reaction of 6.1 withvarious amines can provide the ring opened compounds 6.2 which can becyclized to form intermediates such as 6.3. Displacement of the C2chloride with an amine using a metal catalyst or elevated temperaturecan afford additional compounds of the general formula I.

Additional analogs can be prepared according to the method outlined inScheme 7. Ester 1.7 can be reacted with hydrazine to provide thesubstituted pyridine hydrazide 7.1. Reaction of 7.1 with variousorthoformates in the presence of acid can provide compounds of thegeneral formula I.

Additional heterocycles can be prepared according to the methodsoutlined in Schemes 8 and 9. First, compound 4.1 can be reacted withethyl-2-amino oxamate in the presence of a base, such as TEA, to affordintermediate 8.1 which can be cyclized to intermediate 8.2 by heating athigh temperature in a suitable solvent such as DMF. Amidolysis of thependant ester can afford 8.3 which can be further elaborated uponreaction with an amine at C2 to afford compound of the general formulaI.

In Scheme 9, compound 1.1 can be reduced to alcohol 9.1 using anappropriate hydride source, such as DIBAL, then oxidized to the aldehydeunder standard conditions (COCl)₂, DMSO to furnish 9.2. Intermediate 9.2can be converted to the oxazole upon reaction with Tosmic and a basesuch as K₂CO₃. Reaction with an amine at C2 can fumish additionalcompounds of the general formula I.

EXAMPLES

Preparation of compounds of Formula (I), and intermediates used in thepreparation of compounds of Formula (I), can be prepared usingprocedures shown in the following examples and related procedures. Themethods and conditions used in these examples, and the actual compoundsprepared in these examples, are not meant to be limiting, but are meantto demonstrate how the compounds of Formula (I) can be prepared.Starting materials and reagents used in these examples, when notprepared by a procedure described herein, are generally eithercommercially available, or are reported in the chemical literature, ormay be prepared by using procedures described in the chemicalliterature.

In the examples given, the phrase “dried and concentrated” generallyrefers to drying of a solution in an organic solvent over either sodiumsulfate or magnesium sulfate, followed by filtration and removal of thesolvent from the filtrate (generally under reduced pressure and at atemperature suitable to the stability of the material being prepared).Column chromatography was performed with pre-packed silica gelcartridges using an Isco medium pressure chromatography apparatus(Teledyne Corporation), eluting with the solvent or solvent mixtureindicated. Preparative high performance liquid chromatography (HPLC) wasperformed using a reverse phase column (Waters Sunfire Cis, WatersXbridge Cis, Phenomenex Axia C₁₈, YMC S5 ODS or the like) of a sizeappropriate to the quantity of material being separated, generallyeluting with a gradient of increasing concentration of methanol oracetonitrile in water, also containing 0.05% or 0.1% trifluoroaceticacid or 10 mM ammonium acetate, at a rate of elution suitable to thecolumn size and separation to be achieved. Chemical names weredetermined using ChemDraw Ultra, version 9.0.5 (CambridgeSoft). Thefollowing abbreviations are used:

NaHCO₃ (aq)—saturated aqueous sodium bicarbonatebrine—saturated aqueous sodium chlorideDCM—dichloromethane

DIEA—N,N-diisopropylethylamine DMAP—4-(N,N-dimethylamino)pyridineDMF—N,N-dimethylformamide

DMSO—dimethyl sulfoxideEDC—N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochlorideEtOAc—ethyl acetateHOAT—1-hydroxy-7-azabenzotriazoleHOBT—1-hydroxybenzotriazole hydratert—ambient room temperature (generally about 20-25° C.)TEA—triethylamineTFA—trifluoroacetic acidTHF—tetrahydrofuran

Triazoles

Synthesis of ethyl 6-chloro-4-(isopropylamino)nicotinate (2): A stirredsolution of ethyl 4,6-dichloronicotinate (1) (10 g, 43.4 mmol),isopropyl amine (8 mL) and DIPEA (8 mL) in DMA (50 mL) were heated at120° C. in a sealed tube for 3 h. The reaction mixture was concentratedto dryness to remove excess of DMA from the reaction mass. The crudematerial obtained was purified by column chromatography through silicagel and EtOAC: pet. Ether as eluent to obtain the title compound (2).LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.90 min; LCMS (ES-API), m/z 243.7 (M+H).

Synthesis of 6-chloro-4-(isopropylamino)nicotinic acid (3): Ethyl6-chloro-4-(cyclobutylamino)nicotinate (2) (3 g, 12.3 mmol) in ethanol(20 mL) and water (10 mL) was stirred at rt. LiOH (61.7 mmol, 5 equiv.)was added and the reaction mixture was stirred at room temperature for 4h. The solvent was concentrated under reduced pressure. Diluted withEtOAc and added water. The aqueous layer was collected and acidified topH 3-4 using solid citric acid. Solid material precipitated out.Filtered the solid material and dried under vacuum to furnish the titlecompound (3). ¹H NMR: 400 MHz, DMSO-d₆: δ 1.20 (d, J=6.40 Hz, 6H),3.80-3.88 (m, 1H), 6.80 (s, 1H), 8.20 (d, J=7.60 Hz, 1H), 8.51 (s, 1H),13.33 (bs, 1H).

Synthesis of ethyl6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinate (3): To asolution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2) (5 g, 20.66mmol) in dioxane (30 mL): H₂O (5 mL), 6-amino benzothiazole (20.66 mmol,1 equiv.), xanthphos (8.2 mmol, 0.4 equiv.) and Na₂CO₃ (82.6 mmol, 4equiv.) were added and degassed for 10 min. To the reaction mixturePd₂(dba)₃ (8.2 mmol, 0.4 equiv.) was added and degassed again for 10min. It was then heated at 115° C., overnight. The reaction was cooledand filtered through small pad of celite. The filtrate obtained wasconcentrated to provide crude material. The crude material was purifiedby column chromatography through silica gel and EtOAC: pet. Ether aseluent to afford ethyl6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinate (3). LC/MS:Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water;Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time:0.78 min; LCMS (ES-API), m/z 357.8 (M+H).

Synthesis of 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinicacid (4): Ethyl6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinate (3) (1 g, 2.8mmol) in ethanol (20 mL) and water (5 mL) was stirred at rt then addedLiOH (14 mmol, 5 equiv.). The reaction mixture was stirred at roomtemperature for 4 h, the then heated at 70° C. for 1 h. The solvent wasconcentrated under reduced pressure, diluted with EtOAc and added water.The aqueous layer was collected and acidified to pH 3-4 using solidcitric acid. Solid material precipitated out. Filtered the solidmaterial and dried under vacuum to furnish the title compound (4).LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.65 min; LCMS (ES-API), m/z 329.8 (M+H).

Synthesis of ethyl 2-amino-2-hydrazonoacetate (6): Ethyl2-amino-2-thioxoacetate (5) (5 g, 37.5 mmol) was dissolved in ethanoland cooled to 0° C. Hydrazine in THF (1M, 37.5 mmol) was added dropwiseand stirred at ambient temperature for 1 h. The reaction mixture wasconcentrated, white flakes of ethyl 2-amino-2-hydrazonoacetate wereobtained.

Synthesis of ethyl2-amino-2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinoyl)hydrazono)acetate(7): To a stirred solution of6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinic acid (4) (500mg, 3.8 mmol) and ethyl 2-amino-2-hydrazonoacetate (6) (3.8 mmol, 1equiv.) in DMF (10 mL), HATU (7.63 mmol, 2 equiv.) and DIPEA (15.2 mmol,4 equiv.) were added and stirred for 4 h. The reaction mixture wasconcentrated under reduced pressure to remove excess of DMF. The residueobtained was partitioned between water and EtOAc. The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated. The crudematerial obtained was purified by column chromatography through silicagel and MeOH: CHCl₃ as eluent to afford the title compound.

Example 1

Ethyl2-amino-2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinoyl)hydrazono)acetate(7) (300 mg, 0.679 mmol) was taken in a sealed tube and heated at 180°C. for 1 h. The reaction mass was dissolved in methanol thenconcentrated. The crude material obtained was purified by flash columnchromatography through silica gel and MeOH: CHCl₃ as eluting agents. Thematerial was further purified by prep HPLC to obtainN2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(4H-1,2,4-triazol-3-yl)pyridine-2,4-diamine.¹H NMR: 400 MHz, CD₃OD: δ 1.32 (d, J=4.00 Hz, 6H), 1.43 (t, J=6.80 Hz,3H), 3.72-3.74 (m, 1H), 4.41 (q, J=6.80 Hz, 2H), 6.17 (s, 1H), 7.48 (dd,J=2.40, 8.8 Hz, 1H), 7.93 (d, J=8.80 Hz, 1H), 8.33 (s, 1H), 8.61 (s,1H), 9.02 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 □μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 3 min; retention time: 1.789 min;LCMS (ES-API), m/z 422.0 (M−H). HPLC: XBridge (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 7.569 min; Purity: 99%.

Thiadiazoles

Synthesis of 6-chloro-4-(isopropylamino)nicotinohydrazide (10): To astirred solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2) (3g, 12.39 mmol) in ethanol (10 mL), hydrazine hydrate (3 mL) was addedand refluxed at 80° C. for 3 h. The reaction mixture was cooled andconcentrated to obtain crude compound. The residue obtained wastriturated with diethyl ether and hexane and filtered to get solid,6-chloro-4-(isopropylamino)nicotinohydrazide (10). LC/MS: Acquity BEHC18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1%TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.58 min; LCMS(ES-API), m/z 229.6 (M+H).

Synthesis of methyl2-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-2-oxoacetate(11): To a stirred solution of6-chloro-4-(isopropylamino)nicotinohydrazide (10) (200 mg, 0.35 mmol) inDCM (10 mL), Et₃N (3.1 mmol, 3 equiv) was added and cooled to 0° C.Methyl 2-chloro-2-oxoacetate (0.42 mmol, 1.2 equiv) was added dropwiseand stirred for 6 h at room temperature. The reaction mixture wasquenched with aq. NaHCO₃ solution and extracted in DCM. The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified by column chromatography through silica geland MeOH: DCM as eluent to afford methyl2-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-2-oxoacetate.

Synthesis of methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate(12): To a stirred solution of methyl2-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-2-oxoacetate(11) (1 g, 3.1 mmol) in THF (30 mL), Lawesson's reagent (6.3 mmol, 2equiv) was added and heated to reflux for 3 h. The reaction mixture wasdiluted with EtOAc and washed twice with 10% NaHCO₃ solution. Theorganic layer was collected, dried over Na₂SO₄, filtered andconcentrated. The crude material obtained was purified by columnchromatography through silica gel and MeOH: DCM as eluent afford methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate.

Synthesis of(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone(13): To a stirred solution of methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate(12) (60 mg, 0.1 mmol) in MeOH (2 mL), (S)-Prolinol (0.9 mmol, 5 equiv)was added and refluxed at 80° C. for 1 h. The reaction mixture wascooled and concentrated. The crude material obtained was purified bycolumn chromatography through silica gel and MeOH: DCM as eluent toisolate the desired product,(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone( ). LCMS: XBridge Phe 8, 04.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H₂O:10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100%B over 1.5 min (3.2 min run time); retention time: 1.585 min; LCMS(ES-API), m/z 379.8 (M−H).

Synthesis of5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxamide(14): A solution of methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxylate(12) (200 mg, 0.64 mmol) in MeOH (10 mL) was cooled to −10° C. andNH₃(g) was purged through the reaction mixture for 5 min. The reactionwas heated for 4 h at 80° C., cooled to 0° C. and concentrated to affordthe desired compound,5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxamide.The material was used directly in the next step without purification.

Example 2

Synthesis of(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone.To a solution of(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-(hydroxymethyl)pyrrolidin-1-yl)methanone(27a) (50 mg, 0.15 mmol) in dioxane (5 mL): H₂O (1 mL), 6-aminobenzothiazole (0.18 mmol, 1.2 equiv.), xanthphos (0.07 mmol, 0.5 equiv.)and Na₂CO₃ (0.7 mmol, 3 equiv.) were added and degassed for 10 min. Tothe reaction mixture Pd₂(dba)₃ (0.07 mmol, 0.5 equiv.) was added anddegassed again for 10 min then heated at 115° C., overnight. Thereaction mixture was cooled and filtered through small pad of celite.The filtrate was concentrated and the crude material was purified bycolumn chromatography through silica gel and MeOH: CHCl₃ as eluent. Thematerial was further purified by prep HPLC to afford the title compound.¹H NMR: 400 MHz, CD₃OD: δ 1.38 (d, J=6.40 Hz, 1H), 2.01-2.03 (m, 4H),3.71-3.85 (m, 4H), 3.87-4.23 (m, 2H), 6.22 (s, 1H), 7.57 (dd, J=2.00,8.80 Hz, 1H), 8.15 (d, J=8.80 Hz, 1H), 8.22 (m, 1H), 8.35 (bs, 1H), 9.28(s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 m; Solvent A=10% ACN:90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc;gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.809min; LCMS (ES-API), m/z 496.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 6.317 min; Purity: 96.7%.

Synthesis of Examples 3-18: The method outlined above for Example 2 wasused to prepared Examples 3-18, using appropriate amines. Example 16 wasprepared from compound 14 using the procedures outlined above.

TABLE 1

Example No. R₁ R₂ 2

3

4

5

6

7

8

9

10

11

12

13

14

15

16 NH₂

17

18

Example 3(R)-(5-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.40 Hz, 6H), 1.87-1.99 (m, 2H),3.59-3.70 (m, 2H), 3.77-3.81 (m, 1H), 3.98-4.00 (m, 1H), 4.05-4.20 (m,1H), 4.35-4.42 (m, 1H), 5.07 (s, 1H), 7.61 (dd, J=2.00, −78.20 Hz, 1H),7.97 (d, J=9.20 Hz, 1H), 8.46 (d, J=7.20 Hz, 1H), 8.63 (s, 1H), 8.77 (d,J=1.60 Hz, 1H), 9.76 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 m;Solvent A=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20mM NH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time);retention time: 1.91 min; LCMS (ES-API), m/z 483.0 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:6.869 min; Purity: 98.5%.

Example 4(S)-(5-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.35 (d, J=6.00 Hz, 6H), 1.95-1.98 (m, 2H),3.18 (d, J=5.20 Hz, 3H), 3.60-4.42 (m, 7H), 5.10 (bs, 1H), 6.32 (s, 1H),7.61 (dd, J=2.40, −76.60 Hz, 1H), 7.98 (d, J=9.60 Hz, 1H), 8.47 (d,J=6.80 Hz, 1H), 8.64 (s, 1H), 8.79 (d, J=2.00 Hz, 1H), 9.78 (s, 1H).LC/MS: Purospher@star RP-18, 4×55 mm, 3 m; Solvent A=10% ACN: 90% H₂O:20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient0-100% B over 1.5 min (3.2 min run time); retention time: 1.91 min; LCMS(ES-API), m/z 483.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.86 min; Purity: 95.4%.

Example 5(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.33 (d, J=6.40 Hz, 6H), 1.87-1.99 (m, 2H),3.54-3.79 (m, 3H), 4.00-4.02 (m, 1H), 4.20-4.42 (m, 2H), 5.07 (d, J=3.20Hz, 1H), 6.20 (s, 1H), 7.60 (dd, J=2.40, 9.00 Hz, 1H), 7.98 (d, J=8.80Hz, 1H), 8.40 (d, J=7.20 Hz, 1H), 8.52 (s, 1H), 8.69 (d, J=2.00 Hz, 1H),9.18 (s, 1H), 9.49 (s, 1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 m;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.515 min; LCMS (ES-API), m/z 482.0 (M+H). HPLC: Sunfire C18(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.619 min;Purity: 97.1%.

Example 6(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.00 Hz, 6H), 1.86-1.97 (m, 2H),3.50-3.78 (m, 3H), 4.00-4.01 (m, 2H), 4.01-4.41 (m, 1H), 5.06 (d, J=3.60Hz, 1H), 6.19 (s, 1H), 7.59 (dd, J=2.00, 8.80 Hz, 1H), 7.97 (d, J=9.20Hz, 1H), 8.39 (d, J=6.80 Hz, 1H), 8.51 (s, 1H), 8.67 (d, J=2.00 Hz, 1H),9.17 (s, 1H), 9.40 (s, 1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.510 min; LCMS (ES-API), m/z 482.0 (M+H). HPLC: Sunfire C18(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 30min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 11.92 min;Purity: 98.9%.

Example 7(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.40 Hz, 6H), 1.94-1.97 (m, 2H),3.50-3.78 (m, 3H), 3.97-4.04 (m, 2H), 4.19-4.41 (m, 1H), 5.06 (d, J=3.20Hz, 1H), 6.19 (s, 1H), 7.59 (dd, J=2.00, 8.80 Hz, 1H), 7.97 (d, J=8.80Hz, 1H), 8.39 (d, J=7.20 Hz, 1H), 8.51 (s, 1H), 8.67 (d, J=2.00 Hz, 1H),9.17 (s, 1H), 9.48 (s, 1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.510 min; LCMS (ES-API), m/z 482.2 (M+H). HPLC: Sunfire C18(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 30min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 11.43 min;Purity: 95.1%.

Example 8N-(1-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3-yl)acetamide

¹H NMR: 400 MHz, CD₃OD: δ 1.37-1.38 (m, 6H), 1.94-2.01 (m, 4H),2.15-2.23 (m, 2H), 3.78-3.94 (m, 2H), 4.11-4.15 (m, 1H), 4.25-4.36 (m,2H), 4.45-4.51 (m, 1H), 6.17 (s, 1H), 7.55 (dd, J=2.00, 8.80 Hz, 1H),7.98 (d, J=8.80 Hz, 1H), 8.43 (d, J=1.20 Hz, 1H), 8.50 (d, J=1.60 Hz,1H), 9.09 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10%MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient0-100% B over 2 min (3 min run time); retention time: 1.773 min; LCMS(ES-API), m/z 523.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 5.936 min; Purity: 95.5%.

Example 9(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypiperidin-1-yl)methanone

¹H NMR: 400 MHz, CD₃OD: δ 1.38 (d, J=6.40 Hz, 6H), 1.63-1.72 (m, 2H),1.93-2.06 (m, 2H), 3.60-3.87 (m, 5H), 4.18-4.21 (m, 1H), 4.39-4.42 (m,1H), 6.19 (s, 1H), 7.56 (dd, J=2.00, 8.80 Hz, 1H), 7.98 (d, J=8.80 Hz,1H), 8.42 (s, 1H), 8.49 (s, 1H), 9.09 (s, 1H). LC/MS: XBridge Phe 8,□4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; SolventB=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2min run time); retention time: 1.57 min; LCMS (ES-API), m/z 496.0 (M+H).HPLC: XBridge Phenyl (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 7.131 min; Purity: 95%.

Example 10(4-Aminopiperidin-1-yl)(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanone

¹H NMR: 400 MHz, CD₃OD: δ 1.39 (d, J=6.40 Hz, 6H), 1.67-1.69 (m, 1H),1.78-1.80 (m, 1H), 2.14-2.22 (m, 2H), 3.06-3.02 (m, 1H), 3.33-3.34 (1H,merged with water peak), 3.50-3.54 (m, 1H), 3.88-3.91 (m, 1H), 4.73-4.86(1H, merged with CD₃OD peak), 5.25-5.28 (m, 1H), 6.25 (s, 1H), 7.58 (dd,J=1.60, 8.80 Hz, 1H), 8.16 (d, J=1.60 Hz, 1H), 8.22 (d, J=8.80 Hz, 1H),8.32 (s, 1H), 9.34 (s, 1H). LC/MS: XBridge Phe 8, 04.6×30 mm, 3.5 μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.455 min; LCMS (ES-API), m/z 495.0 (M+H). HPLC: XBridge Phenyl(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.621 min;Purity: 90.7%.

Example 114-((4-(Isopropylamino)-5-(5-(piperazine-1-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)amino)benzonitrile

¹H NMR: 400 MHz, DMSO-d₆: δ 1.31 (d, J=6.00 Hz, 6H), 3.27-3.39 (m, 4H),3.74-3.79 (m, 1H), 3.90 (bs, 2H), 4.41 (bs, 1H), 6.26 (s, 1H), 7.69-7.71(m, 2H), 7.86-7.88 (m, 2H), 8.40-8.42 (m, 1H), 8.54 (s, 1H), 9.09 (bs,1H), 9.81 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.725 min;LCMS (ES-API), m/z 449.0 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 6.055 min; Purity: 91.9%.

Example 12(3-Aminopyrrolidin-1-yl)(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanone

¹H NMR: 400 MHz, CD₃OD: δ 1.36-1.38 (m, 6H), 2.19-2.31 (m, 1H),3.64-3.75 (m, 2H), 3.81-3.97 (m, 3H), 4.22-4.35 (m, 2H), 6.18 (s, 1H),6.68-6.70 (m, 1H), 7.14-7.16 (m, 1H), 7.58 (dd, J=2.00, 26.80 Hz, 1H),7.98 (d, J=8.80 Hz, 1H), 8.42 (s, 1H), 8.48 (d, J=2.00 Hz, 1H), 9.08 (s,1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.70 □μm; Solvent A=2% ACN:98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min; retention time: 1.656 min; LCMS(ES-API), m/z 479.0 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 L/min; Retention time: 5.932 min; Purity: 99.4%.

Example 13N-(1-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3-yl)acetamide

¹H NMR: 400 MHz, CD₃OD: δ 1.37 (d, J=6.40 Hz, 6H), 1.97-2.03 (m, 2H),2.08-2.34 (m, 2H), 3.62-3.65 (m, 1H), 3.78-3.94 (m, 3H), 4.10-4.14 (m,1H), 4.25-4.34 (m, 2H), 4.50-4.57 (m, 2H), 6.18 (s, 1H), 7.55 (dd,J=2.00, 8.80 Hz, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.42 (s, 1H), 8.48 (bs,1H), 8.61 (d, J=7.20 Hz, 1H), 9.08 (s, 1H). LC/MS: XBridge Phe 8,□4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; SolventB=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2min run time); retention time: 1.503 min; LCMS (ES-API), m/z 523.0(M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 5.657 min; Purity: 98.3%.

Example 14

(3-Aminopyrrolidin-1-yl)(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanone

¹H NMR: 400 MHz, CD₃OD: δ 1.37 (d, J=6.00 Hz, 6H), 1.82-1.97 (m, 2H),2.18-2.24 (m, 1H), 3.65-3.74 (m, 2H), 3.80-3.94 (m, 3H), 4.21-4.30 (m,2H), 6.17 (s, 1H), 7.55 (dd, J=2.00, 8.80 Hz, 1H), 7.98 (d, J=8.80 Hz,1H), 8.42 (s, 1H), 8.48 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: XBridgePhe 8, □4.6×30 mm, 3.5 m; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH;Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min(3.2 min run time); retention time: 1.458 min; LCMS (ES-API), m/z 481.2(M+H). HPLC: Eclipse XDB C18 (150×4.6 mm) 5 micron; Solvent A=20 mMNH₄OAc in water; Solvent B=ACN; Flow rate=1.0 mL/min; Retention time:7.946 min; Purity: 90.5%.

Example 15N-(1-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3-yl)methanesulfonamide

¹H NMR: 400 MHz, CD₃OD: δ 1.37-1.38 (m, 6H), 2.00-2.41 (m, 4H),3.04-3.04 (m, 3H), 3.60-4.40 (m, 4H), 4.57 (s, 4H), 6.18 (s, 1H), 7.55(dd, J=2.00, 8.80 Hz, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.43 (s, 1H), 8.48(d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5m; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O:10 mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2 min run time);retention time: 1.576 min; LCMS (ES-API), m/z 559.0 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:6.104 min; Purity: 90.7%.

Example 165-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.00 Hz, 6H), 1.77 (s, 2H),3.72-3.80 (m, 1H), 6.20 (s, 1H), 7.60 (dd, J=2.40, 8.80 Hz, 1H),7.97-7.99 (m, 1H), 8.13 (s, 1H), 8.43 (d, J=7.20 Hz, 1H), 8.52-8.55 (m,2H), 8.69 (d, J=2.00 Hz, 1H), 9.18 (s, 1H), 9.51 (s, 1H). LC/MS: XBridgePhe 8, □4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH;Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min(3.2 min run time); retention time: 1.539 min; LCMS (ES-API), m/z 412.2(M+H). HPLC: XBridge (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 6.653 min; Purity: 94.9%.

Example 174-((5-(5-(4-Hydroxypiperidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile

¹H NMR: 400 MHz, CD₃OD: δ 1.40 (d, J=6.40 Hz, 6H), 1.62-1.70 (m, 2H),2.00-2.04 (m, 2H), 3.48-3.53 (m, 1H), 3.84-3.90 (m, 2H), 4.00-4.03 (m,1H), 4.19-4.22 (m, 1H), 4.80-4.90 (m, 1H), 6.23 (s, 1H), 7.57 (dd,J=2.40, 8.60 Hz, 1H), 8.20 (d, J=1.60 Hz, 1H), 8.31 (s, 1H), 9.30 (s,1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 1.5 min (3.2 min run time); retention time: 1.529 min;LCMS (ES-API), m/z 496.0 (M+H). HPLC: XBridge (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.815 min; Purity: 98.5%.

Example 184-((4-(Isopropylamino)-5-(5-(morpholine-4-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)amino)benzonitrile

¹H NMR: 400 MHz, CDCl₃: δ 1.33 (d, J=6.40 Hz, 6H), 3.66-3.71 (m, 1H),3.81-3.84 (m, 6H), 4.40-4.42 (m, 2H), 6.10 (s, 1H), 6.71 (s, 1H), 7.43(dd, J=2.00, 8.80 Hz, 1H), 8.09-8.12 (m, 2H), 8.40 (s, 1H), 8.56 (d,J=6.40 Hz, 1H), 8.92 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm;Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1%TFA; gradient 0-100% B over 2 min (3 min run time); retention time:1.612 min; LCMS (ES-API), m/z 482.2 (M+H). HPLC: Eclipse XDB C18(150×4.6 mm) 5 micron; Solvent A=20 mM NH₄OAc in water; Solvent B=ACN;Flow rate=1.0 mL/min; Retention time: 10.488 min; Purity: 96%.

Synthesis of (R)-tert-butyl4-((2-chloro-5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-4-yl)amino)benzoate(14): Prepared according to the methods outlined in Example 2 from ethyl4,6-dichloronicotinate (1) and tert-butyl 4-aminobenzoate. LC/MS: ZORBAXSB C18, 4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; SolventB=90% MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3 min runtime); retention time: 2.113 min; LCMS (ES-API), m/z 502.0 (M+H).

Synthesis of(R)-4-((2-chloro-5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-4-yl)amino)benzoicacid (15): Followed the same procedure as mentioned in the synthesis ofcompound no. 2. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; SolventA=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2min; retention time: 0.74 min; LCMS (ES-API), m/z 446.39 (M+H).

Synthesis of(R)-4-((2-chloro-5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-4-yl)amino)-N-methylbenzamide(16): To a stirred solution of(R)-4-((2-chloro-5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-4-yl)amino)benzoicacid (15) (150 mg, 0.336 mmol) in DMF (10 mL), DIPEA (1.682 mmol, 5equiv.), methanamine.HCl (3.36 mmol, 10 equiv.) and HATU (0.673 mmol, 2equiv.) were added at room temperature. The reaction mixture was allowedto stir overnight at ambient temperature. The reaction mixture wasevaporated to remove excess of DMF. The residue obtained was thendiluted with water and extracted using EtOAc. The organic layer wasdried over Na₂SO₄, filtered and evaporated to get crude compound. Thecrude compound was purified by column chromatography through silica geland MeOH: DCM as eluent to isolate the desired compound,(R)-4-((2-chloro-5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-4-yl)amino)-N-methylbenzamide(16). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFAin water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.71 min; LCMS (ES-API), m/z 459.63 (M+H).

Example 19

Synthesis of(R)-4-((2-(benzo[d]thiazol-6-ylamino)-5-(5-(3-hydroxypyrrolidine-1-carbonyl)-1,3,4-thiadiazol-2-yl)pyridin-4-yl)amino)-N-methylbenzamide:Prepared according to the methods outlined in Example 2. ¹H NMR: 400MHz, CD₃OD: δ 1.95 (s, 2H), 2.96 (s, 3H), 3.53-3.54 (m, 1H), 3.74-3.75(m, 1H), 3.83-3.85 (m, 1H), 3.93 (t, J=6.40 Hz, 1H), 4.15-4.24 (m, 1H),6.80 (s, 1H), 7.48 (d, J=8.40 Hz, 2H), 7.55 (dd, J=2.00, 8.80 Hz, 1H),7.91-7.98 (m, 3H), 8.56 (d, J=2.00 Hz, 1H), 8.62 (s, 1H), 9.09 (s, 1H).LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 1.5 min; retention time: 1.71 min; LCMS (ES-API), m/z573.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5%ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFApH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0μL/min; Retention time: 5.148 min; Purity: 96.3%.

Thiazoles

Synthesis of 6-chloro-4-(isopropylamino)nicotinamide (17):6-chloro-4-(isopropylamino)nicotinic acid (9) (3 g, 14 mmol) wasdissolved in DCM (15 mL) and cooled to 0° C. Oxalyl chloride (2 equiv.)was added, followed by addition of 2 drops of DMF. The reaction mixturewas stirred at room temperature for 2 h. The reaction mixture wasconcentrated to remove excess of oxalyl chloride and redissolved in DCM(15 mL) and cooled to 0° C. Aqueous NH₃ solution was added dropwise tothe reaction mixture and stirred at room temperature for 3 h. Thereaction mixture was diluted using DCM and washed with aq. NaHCO₃solution. The organic layer was separately collected, dried over Na₂SO₄,filtered and concentrated to obtain the desired compound,6-chloro-4-(isopropylamino)nicotinamide. LC/MS: Acquity BEH C18 2.1×50mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN;gradient 0-100% B over 2 min; retention time: 0.58 min; LCMS (ES-API),m/z 214.7 (M+H).

Synthesis of 6-chloro-4-(isopropylamino)nicotinonitrile (18): To astirred solution of 6-chloro-4-(isopropylamino)nicotinamide (17) (2.5 g,11.7 mmol) in DMF (10 mL), cyanuric chloride (11.7 mmol, 1 equiv.) wasadded at 0° C. and stirred for 2 h. The reaction mixture was quenchedwith ice-cool water and extracted twice using EtOAc. The organic layerwas collected, dried over Na₂SO₄, filtered and concentrated. The crudematerial was purified by column chromatography, silica gel (60-120 mesh)and EtOAc: pet Ether as eluent to furnish6-chloro-4-(isopropylamino)nicotinonitrile. ¹H NMR: 400 MHz, CDCl₃: δ1.32 (d, J=6.40 Hz, 6H), 3.69-3.79 (m, 1H), 4.91 (bs, 1H), 6.57 (s, 1H),8.23 (s, 1H).

Synthesis of6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinonitrile (19): Toa solution of 6-chloro-4-(isopropylamino)nicotinonitrile (18) (1 g, 5.1mmol) in dioxane (40 mL): H₂O (4 mL), 6-amino benzothiazole (5.1 mmol, 1equiv.), xanthphos (2.0 mmol, 0.4 equiv.) and Na₂CO₃ (20.5 mmol, 4equiv.) were added and degassed for 10 min. To the reaction mixturePd₂(dba)₃ (2.0 mmol, 0.4 equiv.) was added and degassed again for 10min. It was then heated at 115° C. for overnight. The reaction mixturewas cooled and filtered through small pad of celite. The filtrateobtained was concentrated and the crude material was purified by columnchromatography through silica gel and MeOH: CHCl₃ as eluent to afford6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinonitrile.

Synthesis of6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridine-3-carbothioamide(20): To a stirred solution of6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinonitrile (19) (30mg, 0.09 mmol) in MeOH (2 mL), ammonium thiosulfide (5 mL) was added.The reaction mixture was heated at 60° C. in a pressure tube overnight.The reaction mixture was then evaporated to remove excess of solvent.The crude material was purified by column chromatography through silicagel and MeOH: CHCl₃ as eluent to afford6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridine-3-carbothioamide.

Example 20

Synthesis of ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate:6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridine-3-carbothioamide(20) (30 mg, 0.08 mmol) and ethyl bromo pyruvate (0.17 mmol, 2 equiv.)were taken in DMF (5 mL) and heated at 100° C. for 3 h. The reactionmixture was then concentrated under reduced pressure to remove excess ofDMF. The residue was diluted with EtOAc and washed with water. Theaqueous layer was extracted with EtOAc twice. The organic layers werecollected, dried over Na₂SO₄, filtered and concentrated. The crudematerial obtained was purified by column chromatography through silicagel and MeOH: CHCl₃ as eluent to afford ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate.¹H NMR: 400 MHz, CD₃OD: δ 1.34 (d, J=20.00 Hz, 6H), 1.43 (t, J=7.20 Hz,3H), 3.75-3.77 (m, 1H), 4.41 (q, J=7.20 Hz, 2H), 6.16 (s, 1H), 7.54 (dd,J=2.00, 8.8 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.21 (s, 1H), 8.43 (s,1H), 9.07 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 □μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 3 min; retention time: 2.131 min;LCMS (ES-API), m/z 440.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 7.409 min; Purity: 98%.

Example 21

Synthesis of2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxamide:The ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate(Example 20) (200 mg, 0.455 mmol) was taken in a sealed tube, to itmethanol (2 mL) was added, followed by addition of methanolic ammonia(10 mL). The reaction mixture was heated at 80° C. for 3 h. The reactionmixture was concentrated. The crude material was purified by columnchromatography through silica gel and MeOH: CHCl₃ as eluent. Thematerial obtained was further purified on preparative TLC to obtain2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxamide.¹H NMR: 400 MHz, DMSO-d₆: δ 1.33 (d, J=6.40 Hz, 6H), 3.64-3.72 (m, 1H),6.15 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.63 (bs, 1H), 7.69 (bs,1H), 7.95 (d, J=8.80 Hz, 1H), 8.14 (s, 1H), 8.32 (s, 1H), 8.35 (d,J=6.80 Hz, 1H), 8.49 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.15 (s, 1H),9.35 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 □μm; SolventA=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mMNH₄COOH; gradient 0-100% B over 3 min; retention time: 1.933 min; LCMS(ES-API), m/z 411.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 5.137 min; Purity: 99.8%.

Example 22

Synthesis of(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypyrrolidin-1-yl)methanone:The ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate(Example 20) (100 mg, 0.228 mmol) was dissolved in methanol (10 mL) andto it pyrrolidin-3-ol (0.455 mmol, 2 equiv) was added and heated at 80°C. for 2 h. The reaction mixture was concentrated, the crude obtainedwas purified on preparative TLC to obtain(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypyrrolidin-1-yl)methanone.¹H NMR: 400 MHz, DMSO-d₆: δ 1.24 (d, J=4.00 Hz, 6H), 1.85-1.86 (m, 3H),3.46-3.50 (m, 1H), 3.56-3.57 (m, 1H), 3.72-3.73 (m, 1H), 3.90-3.91 (m,1H), 4.35 (bs, 1H), 5.00-5.01 (m, 1H), 6.18 (s, 1H), 7.58 (dd, J=2.00,9.00 Hz, 1H), 7.95-7.97 (m, 1H), 8.13-8.13 (m, 1H), 8.14-8.18 (m, 1H),8.52-8.52 (m, 1H), 8.72-8.72 (m, 1H), 9.16 (s, 1H), 9.37 (s, 1H). LC/MS:Ascentis Express C18, 5×2.1 mm-2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mMNH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 3 min; retention time: 1.883 min; LCMS (ES-API), m/z 481.2 (M+H).HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O:0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retentiontime: 5.062 min; Purity: 92.2%.

Synthesis of 6-chloro-4-(isopropylamino)pyridine-3-carbothioamide (21):Followed the same procedure as mentioned in the synthesis of Example 20.

Synthesis of ethyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate (22a):Followed the same procedure as mentioned in the synthesis of Example 20.

Synthesis of ethyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylate(22b): Followed the same procedure as mentioned in the synthesis ofExample 20, instead of ethyl bromo pyruvate (2 equiv.), methyl ethylbromo pyruvate (2 equiv.) was used.

Example 23

Ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylate

¹H NMR: 400 MHz, DMSO-d₆: δ 1.31-1.37 (m, 6H), 1.41-1.46 (m, 3H), 2.80(s, 1H), 3.76-3.79 (m, 1H), 4.35 (q, J=7.20 Hz, 2H), 6.15 (s, 1H), 7.53(dd, J=2.00, 8.80 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.31 (s, 1H), 8.41(d, J=2.00 Hz, 1H), 9.07 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5□μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O:0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time:2.249 min; LCMS (ES-API), m/z 454.0 (M+H). HPLC: Sunfire C18 (150×4.6mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; SolventB=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23min run time); Flow rate: 1.0 μL/min; Retention time: 7.622 min; Purity:88.2%.

Synthesis of2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylic acid(23a): Followed the same procedure as mentioned in the synthesis ofcompound no. 9.

2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylicacid (23b): Followed the same procedure as mentioned in the synthesis ofcompound no. 9.

Synthesis of(2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone(24a): The2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylic acid(23a) (100 mg, 0.336 mmol) was dissolved in DMF (5 mL), piperidin-3-ol(1.679 mmol) was added and stirred at room temperature. Added DIPEA(1.343 mmol), followed by addition of HATU (1.008 mmol) and stirred for3 h. The reaction mixture was concentrated under reduced pressure toremove excess of DMF. The residue obtained was partitioned between waterand EtOAc. The organic layer was separated, dried over Na₂SO₄, filteredand concentrated. The crude material obtained was purified by columnchromatography through silica gel and MeOH: CHCl₃ as eluent to affordthe title compound,(2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone.

Synthesis of2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyl-N-(3-(piperidin-1-yl)propyl)thiazole-4-carboxamide(24b): Followed the same procedure as mentioned in the synthesis ofcompound no. 24a, instead of piperidin-3-ol,3-(piperidin-1-yl)propan-1-amine was used.

Synthesis of 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)5-methylthiazole-4-carboxamide (24c): Followed the same procedure asmentioned in the synthesis of compound no. 24a, instead ofpiperidin-3-ol, ammonium chloride was used.

Synthesis of 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)5-methylthiazole-4-methyl carboxamide (24d): Followed the same procedureas mentioned in the synthesis of compound no. 24a, instead ofpiperidin-3-ol, methyl amine was used.

TABLE 2

Example No. R R₁ 24 H

25 CH₃

26 CH₃ NH₂

Synthesis of(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone(Example 24):(2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone(24a) (100 mg, 0.263 mmol) was dissolved in 1,4-Dioxane (10 mL): H₂O (2mL), to it benzo[d]thiazol-6-amine (0.263 mmol), Na₂CO₃ (1.05 mmol) andxanthphos (0.105 mmol) were added and degassed for 10 min. Pd₂(dba)₃(0.105 mmol) was added and degassed once again for 15 min and heated at115° C., overnight. The reaction mass was filtered through celite andconcentrated to remove solvent. The crude material obtained was purifiedby column chromatography through silica gel and MeOH: CHCl₃ as eluent.The material obtained was further purified by prep. HPLC to obtain thetitle compound,(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone.¹H NMR: 400 MHz, CD₃OD: δ 0.87-0.94 (m, 1H), 1.31-1.36 (m, 6H),1.62-0.00 (m, 2H), 1.92-2.03 (m, 2H), 3.42-3.43 (m, 1H), 3.75-3.98 (m,4H), 6.16 (s, 1H), 7.54 (dd, J=2.00, 8.80 Hz, 1H), 7.79 (bs, 1H), 7.91(s, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.43 (d, J=2.40 Hz, 1H), 8.45 (s, 1H),9.07 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 □μm; SolventA=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mMNH₄COOH; gradient 0-100% B over 3 min; retention time: 1.754 min; LCMS(ES-API), m/z 495.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 5.431 min; Purity: 96.29%.

Synthesis of2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyl-N-(3-(piperidin-1-yl)propyl)thiazole-4-carboxamide(Example 25): Followed the same procedure as mentioned in the synthesisof Example 24. ¹H NMR: 400 MHz, DMSO-d₆: δ 1.33 (d, J=6.40 Hz, 6H),1.50-1.91 (m, 8H), 2.20-2.34 (m, 2H), 2.545 (2H, merged with DMSO-d₆peak), 2.75 (s, 3H), 3.00-3.15 (m, 4H), 3.64-3.69 (m, 1H), 6.14 (s, 1H),7.58 (dd, J=2.40, 9.00 Hz, 1H), 7.95 (d, J=9.20 Hz, 1H), 8.19 (d, J=5.60Hz, 1H), 8.37 (s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.34 (s,1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 □μm; Solvent A=2% ACN:98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 3 min; retention time: 1.766 min; LCMS (ES-API),m/z 550.2 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5 micron; SolventA=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05%TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate:1.0 μL/min; Retention time: 10.867 min; Purity: 96.2%.

Synthesis of2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxamide(Example 26): Followed the same procedure as mentioned in the synthesisof Example 24. ¹H NMR: 400 MHz, CDCl₃: δ 1.28-1.34 (m, 6H), 2.01-2.11(m, 2H), 2.84 (s, 3H), 3.62-3.67 (m, 1H), 5.54-5.57 (m, 1H), 6.08 (bs,1H), 6.69 (bs, 1H), 7.42 (dd, J=2.00, 8.80 Hz, 1H), 8.06-8.09 (m, 2H),8.29 (bs, 2H), 8.90 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7□μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2%H₂O: 10 mM NH₄COOH; gradient 0-100% B over 3 min; retention time: 1.846min; LCMS (ES-API), m/z 423.0 (M−H). HPLC: XBridge (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 6.399 min; Purity: 73.5%.

Synthesis of2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylicacid (25a) and2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylicacid (25b): Followed the same procedure as mentioned in the synthesis ofcompound no. 9.

Example 27

Synthesis of2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N,5-dimethylthiazole-4-carboxamide(Example 27).2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylicacid (25b) was dissolved in DMF (10 mL), to it methanamine (1 equiv.)was added followed by the addition of HATU (1.5 equiv.) and DIPEA (4equiv.) and stirred for 3 h at room temperature. The reaction mixturewas concentrated to remove DMF under reduced pressure. The crudematerial obtained was purified by flash column chromatography usingsilica gel and MeOH: CHCl₃ as eluent. The material obtained wastriturated with diethyl ether and hexane to afford ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methylthiazole-4-carboxylate.¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.40 Hz, 6H), 2.73 (s, 3H), 2.81(d, J=4.40 Hz, 3H), 3.64-3.69 (m, 1H), 6.13 (s, 1H), 7.58 (dd, J=2.00,8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.13 (d, J=4.80 Hz, 1H), 8.20 (d,J=7.20 Hz, 1H), 8.37 (s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.15 (s, 1H),9.33 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10%MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient0-100% B over 2 min (3 min run time); retention time: 1.606 min; LCMS(ES-API), m/z 439.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.323 min; Purity: 96.3%.

Synthesis of Examples 28-85: Followed the same procedure as mentioned inthe synthesis of compound Example 27.

TABLE 3

Example No. R₁ 28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

Example 28(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.28-1.30 (m, 6H), 1.42-1.44 (m, 2H),1.65-1.75 (m, 4H), 1.85-1.99 (m, 5H), 2.33-2.34 (m, 1H), 2.52 (1H,merged with DMSO-d₆ peak), 3.04 (bs, 1H), 3.68-3.76 (m, 1H), 3.98-4.28(m, 2H), 6.16 (s, 1H), 7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.92-7.97 (m,2H), 8.36 (d, J=7.20 Hz, 1H), 8.52 (s, 1H), 8.72 (d, J=2.40 Hz, 1H),9.16 (s, 1H), 9.36 (s, 1H). Mol. wt.: 547.74. LC/MS: Retention time:1.895 min. Purity: 99.7%.

Example 29(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-((1Z,3E)-1-(methyleneamino)penta-1,3-dien-3-yl)piperazin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.28 (m, 6H), 3.46 (bs, 4H), 3.69-3.74(m, 1H), 3.82 (bs, 4H), 6.17 (s, 1H), 6.86 (d, J=6.00 Hz, 2H), 7.59 (dd,J=2.40, 9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.04 (s, 1H), 8.20 (d,J=5.20 Hz, 2H), 8.31 (d, J=6.80 Hz, 1H), 8.54 (s, 1H), 8.72 (d, J=2.00Hz, 1H), 9.16 (s, 1H), 9.38 (s, 1H). Mol. wt.: 556.71. LC/MS: Retentiontime: 1.956 min. Purity: 99.4%.

Example 301-(4-(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carbonyl)-1,4-diazepan-1-yl)ethanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.27-1.29 (m, 6H), 1.62-1.91 (m, 3H),2.01-2.08 (m, 2H), 3.50-3.80 (m, 9H), 6.16 (s, 1H), 7.57-7.60 (m, 1H),7.93-7.98 (m, 2H), 8.18-8.27 (m, 1H), 8.51 (s, 1H), 8.72 (s, 1H), 9.16(s, 1H), 9.36 (s, 1H). Mol. wt.: 535.68. LC/MS: Retention time: 1.93min. Purity: 97%.

Example 31(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(2,4-difluorophenyl)piperazin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.29 (d, J=6.40 Hz, 6H), 3.04 (s, 4H),3.70-3.75 (m, 1H), 3.83-3.84 (m, 4H), 6.17 (s, 1H), 7.01-7.13 (m, 2H),7.21-7.27 (m, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.96 (d, J=8.80 Hz,1H), 8.03 (s, 1H), 8.35 (bs, 1H), 8.52 (s, 1H), 8.71 (s, 1H), 9.16 (s,1H), 9.39 (s, 1H). Mol. wt.: 591.7. LC/MS: Retention time: 2.962 min.Purity: 99.5%.

Example 32(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.28 (m, 6H), 3.71-3.84 (m, 9H), 6.17(s, 1H), 6.69 (t, J=4.80 Hz, 1H), 7.59 (dd, J=2.40, 8.80 Hz, 1H), 7.96(d, J=8.80 Hz, 1H), 8.03 (s, 1H), 8.31 (d, J=7.20 Hz, 1H), 8.41 (d,J=4.80 Hz, 2H), 8.53 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.16 (s, 1H),9.37 (s, 1H). Mol. wt.: 557.69. LC/MS: Retention time: 2.483 min.Purity: 96%.

Example 33(4-(Benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.28-1.30 (m, 6H), 2.41-2.43 (m, 4H), 3.45(s, 2H), 3.62-3.64 (m, 4H), 3.65-3.75 (m, 1H), 6.00 (s, 2H), 6.16 (s,1H), 6.76-6.78 (m, 1H), 6.85-6.89 (m, 2H), 7.58 (dd, J=2.00, 9.00 Hz,1H), 7.95-7.97 (m, 2H), 8.31 (dd, J=7.20, Hz, 1H), 8.52 (s, 1H), 8.72(dd, J=2.00, Hz, 1H), 9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 613.75.LC/MS: Retention time: 2.748 min. Purity: 98.8%.

Example 343-(4-(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carbonyl)piperazin-1-yl)propanenitrile

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30 (d, J=6.40 Hz, 6H), 2.63-2.73 (m, 4H),3.67-3.73 (m, 5H), 6.17 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H),7.95-7.98 (m, 2H), 8.32-8.34 (m, 1H), 8.52 (s, 1H), 8.72 (d, J=2.00 Hz,1H), 9.16 (s, 1H), 9.38 (s, 1H). Mol. wt.: 532.68. LC/MS: Retentiontime: 2.146 min. Purity: 98.5%.

Example 35(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(pyrazin-2-yl)piperazin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.28 (d, J=6.00 Hz, 6H), 3.69-3.72 (m, 5H),3.82 (bs, 4H), 6.17 (s, 1H), 7.59 (dd, J=2.00, 8.80 Hz, 1H), 7.89 (d,J=2.80 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.04 (s, 1H), 8.12-8.13 (m,1H), 8.31 (d, J=7.20 Hz, 1H), 8.36 (d, J=1.20 Hz, 1H), 8.54 (s, 1H),8.72 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 557.69.LC/MS: Retention time: 2.277 min. Purity: 95.4%.

Example 361-(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carbonyl)piperidine-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.29 (d, J=6.40 Hz, 1H), 1.50-1.58 (m, 2H),1.78-1.80 (m, 2H), 2.40-2.46 (m, 1H), 2.88 (bs, 1H), 3.18 (bs, 1H),3.69-3.74 (m, 1H), 4.07 (bs, 1H), 4.44 (bs, 1H), 6.17 (s, 1H), 6.80 (bs,1H), 7.30 (bs, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.94-7.97 (m, 2H),8.36 (d, J=6.80 Hz, 1H), 8.52 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.16 (s,1H), 9.37 (s, 1H). Mol. wt.: 521.66. LC/MS: Retention time: 1.831 min.Purity: 99.1%.

Example 37(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(2-hydroxyethyl)piperidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.05-1.14 (m, 2H), 1.29 (d, J=6.40 Hz, 6H),1.37-1.42 (m, 2H), 1.65-1.72 (m, 3H), 2.67-3.10 (m, 3H), 3.44-3.49 (m,2H), 3.70-3.75 (m, 1H), 4.01-4.10 (m, 1H), 4.38 (t, J=5.20 Hz, 1H), 4.45(bs, 1H), 6.16 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.90 (s, 1H),7.96 (d, J=8.80 Hz, 1H), 8.37 (d, J=7.20 Hz, 1H), 8.51 (s, 1H), 8.72 (d,J=2.00 Hz, 1H), 9.16 (s, 1H), 9.36 (s, 1H). Mol. wt.: 522.69. LC/MS:Retention time: 2.059 min. Purity: 95.4%.

Example 382-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-cyanoethyl)-N-methylthiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.28 (d, J=6.00 Hz, 6H), 2.85-2.91 (m, 2H),3.71-3.90 (m, 3H), 6.16 (s, 1H), 7.57 (dd, J=2.40, 8.80 Hz, 1H),7.95-8.05 (m, 2H), 8.43-8.51 (m, 2H), 8.69 (s, 1H), 9.17 (s, 1H), 9.40(s, 1H). Mol. wt.: 477.61. LC/MS: Retention time: 2.166 min. Purity:99.5%.

Example 39(S)-(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.29 (m, 6H), 1.81-2.03 (m, 4H), 3.17(bs, 1H), 3.50-3.64 (m, 2H), 3.71-3.85 (m, 2H), 4.22 (bs, 1H), 4.81 (bs,1H), 6.17 (s, 1H), 7.58 (dd, J=2.40, 9.00 Hz, 1H), 7.96 (d, J=9.20 Hz,1H), 8.11 (s, 1H), 8.30-8.32 (m, 1H), 8.51 (s, 1H), 8.71 (d, J=2.00 Hz,1H), 0.00 (s, 1H), 9.37 (s, 1H). Mol. wt.: 494.63. LC/MS: Retentiontime: 2.109 min. Purity: 98.1%.

Example 40(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30 (d, J=6.00 Hz, 6H), 2.42-2.51 (m, 3H),3.51-3.55 (m, 2H), 3.64-3.75 (m, 5H), 4.44-4.45 (m, 1H), 6.16 (s, 1H),7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.95-7.97 (m, 2H), 8.33 (d, J=7.20 Hz,1H), 8.52 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.36 (s, 1H).Mol. wt.: 523.67. LC/MS: Retention time: 1.849 min. Purity: 98.1%.

Example 41(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-hydroxy-4-phenylpiperidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.25-1.26 (m, 6H), 1.69-1.74 (m, 2H),1.91-1.96 (m, 2H), 3.31 (1H, merged with water peak), 3.59 (bs, 1H),3.68-3.73 (m, 1H), 4.01 (bs, 1H), 4.47 (bs, 1H), 5.23 (s, 1H), 6.16 (s,1H), 7.22-7.26 (m, 1H), 7.32-7.36 (m, 2H), 7.50-7.52 (m, 2H), 7.58 (dd,J=2.40, 8.80 Hz, 1H), 7.95-7.98 (m, 2H), 8.38 (dd, J=7.20, Hz, 1H), 8.51(s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.:570.73. LC/MS: Retention time: 2.477 min. Purity: 98.2%.

Example 42(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(pyridin-2-yl)piperazin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.27 (d, J=6.40 Hz, 6H), 3.60 (bs, 4H),3.69-3.74 (m, 1H), 3.78-3.80 (m, 4H), 6.17 (s, 1H), 6.69 (dd, J=4.80,6.60 Hz, 1H), 6.87 (d, J=8.80 Hz, 1H), 7.56-7.60 (m, 2H), 7.96 (d,J=9.20 Hz, 1H), 8.03 (s, 1H), 8.15 (dd, J=1.20, 4.80 Hz, 1H), 8.34 (d,J=6.80 Hz, 1H), 8.53 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 0.00 (s, 1H),9.38 (s, 1H). Mol. wt.: 556.71. LC/MS: Retention time: 1.55 min. Purity:96%.

Example 432-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-methyl-N-(pyridin-3-ylmethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.21 (d, J=6.40 Hz, 6H), 2.94-3.15 (m, 3H),3.66-3.71 (m, 1H), 4.76-4.92 (m, 2H), 6.15 (s, 1H), 7.40-7.41 (m, 1H),7.57 (dd, J=2.00, 8.80 Hz, 1H), 7.76 (bs, 1H), 7.96 (d, J=8.80 Hz, 1H),8.04-8.08 (m, 1H), 8.41-8.60 (m, 3H), 8.70 (d, J=1.60 Hz, 1H), 9.16 (s,1H), 9.37 (s, 1H). Mol. wt.: 515.65. LC/MS: Retention time: 2.197 min.Purity: 99.9%.

Example 44(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(2-morpholinoethyl)piperazin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30 (d, J=6.00 Hz, 6H), 2.50 (4H, mergedwith DMSO-d₆ peak), 2.99 (bs, 2H), 3.30 (5H, merged with water peak),3.57-3.75 (m, 9H), 6.17 (s, 1H), 7.59 (dd, J=2.00, 8.80 Hz, 1H),7.95-7.97 (m, 2H), 8.33 (d, J=7.20 Hz, 1H), 8.52 (s, 1H), 8.72 (d,J=2.40 Hz, 1H), 9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 592.78. LC/MS:Retention time: 2.008 min. Purity: 96%.

Example 45(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-benzoylpiperazin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.29 (m, 6H), 3.71-3.78 (m, 9H), 6.16(s, 1H), 7.46-7.48 (m, 5H), 7.58 (dd, J=2.40, 9.00 Hz, 1H), 7.96 (d,J=8.80 Hz, 1H), 8.04 (s, 1H), 8.24 (bs, 1H), 8.51 (s, 1H), 8.71 (d,J=1.20 Hz, 1H), 9.16 (s, 1H), 9.38 (s, 1H). Mol. wt.: 583.73. LC/MS:Retention time: 2.352 min. Purity: 97.6%.

Example 46(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(2-(hydroxymethyl)piperidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.28-1.30 (m, 6H), 1.31-1.43 (m, 5H),2.75-3.15 (m, 1H), 3.41-3.59 (m, 2H), 3.68-3.76 (m, 1H), 4.06-4.34 (m,1H), 4.73-4.78 (m, 1H), 6.16 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H),7.83 (bs, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.43 (bs, 1H), 8.51 (s, 1H),8.72 (d, J=2.00 Hz, 1H), 0.00 (s, 1H), 9.35 (s, 1H). Mol. wt.: 508.66.LC/MS: Retention time: 2.196 min. Purity: 95.2%.

Example 47(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-morpholinopyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.31 (m, 6H), 1.71-1.91 (m, 1H),2.10-2.20 (m, 1H), 2.50-0.00 (m, 5H), 2.80-2.90 (m, 1H), 3.45-3.62 (m,5H), 3.70-3.85 (m, 2H), 4.08-4.10 (m, 1H), 6.17 (s, 1H), 6.51 (s, 2H),7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.12 (d,J=14.80 Hz, 1H), 8.17-8.30 (m, 1H), 8.52 (d, J=2.00 Hz, 1H), 8.72 (d,J=2.40 Hz, 1H), 9.16 (s, 1H), 9.36 (s, 1H). Mol. wt.: 549.71. LC/MS:Retention time: 2.124 min. Purity: 96.8%.

Example 488-(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carbonyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one

¹H NMR: 400 MHz, DMSO-d₆: δ 1.25 (d, J=6.00 Hz, 6H), 1.79 (bs, 2H),2.38-2.41 (m, 1H), 2.50 (1H, merged with DMSO-d₆ peak), 3.59 (bs, 1H),3.66-3.74 (m, 1H), 3.96 (s, 1H), 4.23 (bs, 1H), 4.42 (bs, 1H), 4.63 (s,2H), 6.16 (s, 1H), 6.78-6.82 (m, 3H), 7.24-7.28 (m, 2H), 7.58 (dd,J=2.40, 9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.07 (s, 1H), 8.32 (d,J=7.20 Hz, 1H), 8.52 (s, 1H), 8.72 (d, J=2.40 Hz, 1H), 8.83 (s, 1H),9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 624.78. LC/MS: Retention time:2.485 min. Purity: 98.3%.

Example 49(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-benzyl-4-hydroxypiperidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.27 (d, J=6.00 Hz, 6H), 1.40-1.51 (m, 4H),2.73 (s, 2H), 3.15 (s, 1H), 3.44-3.41 (m, 1H), 3.69-3.74 (m, 1H),3.89-3.91 (m, 1H), 4.21-4.25 (m, 1H), 4.55 (s, 1H), 6.16 (s, 1H),7.18-7.29 (m, 5H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.91 (s, 1H), 7.96(d, J=8.80 Hz, 1H), 8.32 (d, J=7.20 Hz, 1H), 8.50 (s, 1H), 8.71 (d,J=2.00 Hz, 1H), 9.16 (s, 1H), 9.36 (s, 1H). Mol. wt.: 584.76. LC/MS:Retention time: 2.578 min. Purity: 97.9%.

Example 50(R)-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.27-1.29 (m, 6H), 1.81-2.03 (m, 4H), 3.18(s, 1H), 3.50-3.64 (m, 2H), 3.71-3.85 (m, 3H), 4.22 (bs, 1H), 4.81 (bs,1H), 6.17 (s, 1H), 7.58 (dd, J=2.40, 8.80 Hz, 1H), 7.96 (d, J=8.80 Hz,1H), 8.11 (s, 1H), 8.20-8.32 (m, 1H), 8.51 (s, 1H), 8.71 (d, J=1.60 Hz,1H), 9.16 (s, 1H), 9.38 (s, 1H). Mol. wt.: 494.63. LC/MS: Retentiontime: 2.141 min. Purity: 99.7%.

Example 51(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.25-1.26 (m, 6H), 1.67-1.74 (m, 2H),1.92-2.00 (m, 2H), 3.18-3.26 (m, 2H), 3.70-3.78 (m, 2H), 3.98-3.99 (m,1H), 4.43-4.48 (m, 1H), 5.32-5.34 (m, 1H), 6.18 (s, 1H), 7.39-7.41 (m,2H), 7.52-7.57 (m, 3H), 8.04-8.08 (m, 2H), 8.43 (s, 1H), 8.51 (bs, 1H),8.71 (bs, 1H), 9.27 (s, 1H), 9.66 (bs, 1H). Mol. wt.: 605.17. LC/MS:Retention time: 2.695 min. Purity: 99.1%.

Example 522-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-methyl-N-(prop-2-yn-1-yl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.29 (d, J=6.40 Hz, 6H), 2.50 (1H, mergedwith DMSO-d₆ peak), 3.09-3.23 (m, 3H), 3.68-3.76 (m, 1H), 4.35-4.49 (m,2H), 6.17 (s, 1H), 7.58 (dd, J=2.40, 8.80 Hz, 1H), 7.96 (d, J=8.80 Hz,1H), 8.05-8.42 (m, 2H), 8.53 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.16 (s,1H), 9.37 (s, 1H). Mol. wt.: 462.59. LC/MS: Retention time: 2.419 min.Purity: 96.2%.

Example 53(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(pyrimidin-2-yl)-1,4-diazepan-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.21-1.29 (m, 6H), 1.80-1.81 (m, 1H),1.91-1.92 (m, 1H), 3.63-3.73 (m, 3H), 3.82-3.95 (m, 6H), 6.15-6.17 (m,1H), 6.51-6.64 (m, 1H), 7.57-7.59 (m, 1H), 7.65-7.88 (m, 1H), 7.96 (d,J=9.20 Hz, 1H), 8.16-8.38 (m, 3H), 8.50-8.51 (m, 1H), 8.71 (s, 1H), 9.16(s, 1H), 9.37 (s, 1H). Mol. wt.: 571.72. LC/MS: Retention time: 2.466min. Purity: 97.4%.

Example 54(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(3-hydroxypropyl)piperazin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30 (d, J=6.00 Hz, 6H), 1.58-1.63 (m, 2H),2.33-2.42 (m, 6H), 3.43-3.46 (m, 2H), 3.62-3.65 (m, 4H), 3.70-3.75 (m,1H), 6.16 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.96 (t, J=4.40 Hz,2H), 8.33 (d, J=7.20 Hz, 1H), 8.52 (s, 1H), 8.72 (d, J=2.40 Hz, 1H),9.16 (s, 1H), 9.36 (s, 1H). Mol. wt.: 537.7. LC/MS: Retention time:1.935 min. Purity: 99.1%.

Example 55(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(4-(pyridin-2-yl)-1,4-diazepan-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.22-1.30 (m, 6H), 1.80-1.82 (m, 1H),1.91-1.96 (m, 1H), 2.50 (1H, merged with DMSO-d₆ peak), 3.44-3.47 (m,1H), 3.57-3.61 (m, 2H), 3.70-3.76 (m, 3H), 3.83 (bs, 3H), 6.16-6.17 (m,1H), 6.51-6.74 (m, 2H), 7.45-7.60 (m, 2H), 7.89-7.97 (m, 2H), 8.09-8.19(m, 1H), 8.31 (d, J=6.80 Hz, 1H), 8.51 (bs, 1H), 8.72 (bs, 1H), 9.16 (s,1H), 9.37 (bs, 1H). Mol. wt.: 570.73. LC/MS: Retention time: 2.62 min.Purity: 99.4%.

Example 562-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(cyclohexylmethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.94-0.97 (m, 2H), 1.16-1.24 (m, 3H), 1.33(d, J=6.40 Hz, 6H), 1.64-1.76 (m, 6H), 3.16 (t, J=6.40 Hz, 2H),3.66-3.71 (m, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.40, 8.80 Hz, 1H), 7.96(d, J=9.20 Hz, 1H), 8.11 (s, 1H), 8.22 (t, J=6.00 Hz, 1H), 8.33 (d,J=6.40 Hz, 1H), 8.49 (s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.16 (s, 1H),9.37 (s, 1H). Mol. wt.: 506.69. LC/MS: Retention time: 3.040 min.Purity: 97.2%.

Example 572-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.40 Hz, 6H), 1.42-1.49 (m, 2H),1.60-1.65 (m, 2H), 1.99-2.12 (m, 2H), 2.20-2.23 (m, 3H), 2.52 (2H,merged with DMSO-d₆ peak), 2.98 (bs, 2H), 3.66-3.71 (m, 1H), 6.15 (s,1H), 7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.11 (s,1H), 8.31-8.33 (m, 2H), 8.49 (s, 1H), 8.72 (d, J=2.40 Hz, 1H), 9.15 (s,1H), 9.36 (s, 1H). Mol. wt.: 521.7. LC/MS: Retention time: 2.202 min.Purity: 95.4%.

Example 582-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-(pyrrolidin-1-yl)ethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.33 (d, J=6.00 Hz, 6H), 1.71 (bs, 4H), 2.50(4H, merged with DMSO-d₆ peak), 2.55-2.64 (m, 2H), 3.43-3.47 (m, 2H),3.69-3.71 (m, 1H), 6.16 (s, 1H), 7.58 (dd, J=2.00, 9.00 Hz, 1H),7.95-7.99 (m, 2H), 8.15 (s, 1H), 8.28 (s, 1H), 8.50 (s, 1H), 8.72 (d,J=2.00 Hz, 1H), 9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 507.67. LC/MS:Retention time: 2.386 min. Purity: 96.9%.

Example 592-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-((tetrahydrofuran-2-yl)methyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.00 Hz, 6H), 1.57-1.62 (m, 1H),1.82-1.96 (m, 3H), 3.35 (2H, merged with water peak), 3.40-3.44 (m, 1H),3.64-3.71 (m, 2H), 3.77-3.80 (m, 1H), 3.97-3.99 (m, 1H), 6.16 (s, 1H),7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.03 (t, J=6.00Hz, 1H), 8.16 (s, 1H), 8.29 (d, J=7.20 Hz, 1H), 8.50 (s, 1H), 8.72 (d,J=2.00 Hz, 1H), 9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 494.63. LC/MS:Retention time: 2.399 min. Purity: 97.7%.

Example 602-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(sec-butyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.90 (t, J=7.20 Hz, 3H), 1.18 (d, J=6.80 Hz,3H), 1.29-1.34 (m, 6H), 1.51-1.59 (m, 2H), 3.67-3.72 (m, 1H), 3.88-3.93(m, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.94-7.98 (m,2H), 8.13 (s, 1H), 8.44-8.52 (m, 2H), 8.68 (bs, 1H), 9.18 (s, 1H), 9.42(bs, 1H). Mol. wt.: 466.62. LC/MS: Retention time: 2.644 min. Purity:99.6%.

Example 612-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-neopentylthiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.82 (s, 2H), 0.93 (s, 9H), 1.32 (d, J=6.00Hz, 6H), 3.15-3.18 (m, 2H), 3.71-3.74 (m, 1H), 6.17 (s, 1H), 7.57 (dd,J=2.00, 8.80 Hz, 1H), 8.00 (d, J=8.80 Hz, 1H), 8.14-8.19 (m, 2H),8.46-8.50 (m, 2H), 8.61 (bs, 1H), 9.21 (s, 1H), 9.56 (bs, 1H). Mol. wt.:480.65. LC/MS: Retention time: 2.832 min. Purity: 95%.

Example 622-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-isobutylthiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.92 (d, J=6.80 Hz, 6H), 1.33 (d, J=6.40 Hz,6H), 1.83-1.88 (m, 1H), 3.14 (t, J=6.40 Hz, 2H), 3.66-3.71 (m, 1H), 6.16(s, 1H), 7.58 (dd, J=2.40, 9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.12(s, 1H), 8.26 (t, J=6.00 Hz, 1H), 8.33 (d, J=6.80 Hz, 1H), 8.49 (s, 1H),8.71 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 466.62.LC/MS: Retention time: 2.645 min. Purity: 96.3%.

Example 632-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-ethylthiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.16 (t, J=7.20 Hz, 3H), 1.34 (d, J=6.40 Hz,6H), 3.35 (2H, merged with water peak), 3.66-3.71 (m, 1H), 6.15 (s, 1H),7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.11 (s, 1H),8.24-8.26 (m, 1H), 8.39 (d, J=6.80 Hz, 1H), 8.49 (s, 1H), 8.72 (d,J=2.00 Hz, 1H), 9.15 (s, 1H), 9.36 (s, 1H). Mol. wt.: 438.57. LC/MS:Retention time: 2.298 min. Purity: 98.1%.

Example 64N-(2-Acetamidoethyl)-2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.35 (d, J=6.40 Hz, 6H), 1.82 (s, 3H),3.22-3.38 (m, 4H), 3.67-3.72 (m, 1H), 6.16 (s, 1H), 7.58 (dd, J=2.00,9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.04-8.05 (m, 1H), 8.14 (s, 1H),8.32-8.36 (m, 2H), 8.49 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.16 (s, 1H),9.36 (s, 1H). Mol. wt.: 495.62. LC/MS: Retention time: 1.834 min.Purity: 99.6%.

Example 652-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-(dimethylamino)ethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.00 Hz, 6H), 2.24 (bs, 6H), 2.52(2H, merged with DMSO-d₆ peak), 3.41-3.46 (m, 2H), 3.68-3.73 (m, 1H),6.16 (s, 1H), 7.59 (dd, J=2.40, 8.80 Hz, 1H), 7.91-7.97 (m, 2H), 8.15(s, 1H), 8.25 (d, J=6.80 Hz, 1H), 8.50 (s, 1H), 8.71 (d, J=2.00 Hz, 1H),9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 481.64. LC/MS: Retention time:2.269 min. Purity: 95.9%.

Example 662-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-methoxyethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.40 Hz, 6H), 3.29 (3H, mergedwith water peak), 3.48-3.50 (m, 4H), 3.67-3.70 (m, 1H), 6.16 (s, 1H),7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.04-8.07 (m,1H), 8.15 (s, 1H), 8.32 (d, J=6.80 Hz, 1H), 8.50 (s, 1H), 8.72 (d,J=2.00 Hz, 1H), 9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 468.6. LC/MS:Retention time: 2.243 min. Purity: 96.6%.

Example 672-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(4-hydroxyphenethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.29 (d, J=6.40 Hz, 6H), 2.73-2.77 (m, 2H),3.47-3.51 (m, 2H), 3.66-3.71 (m, 1H), 6.15 (s, 1H), 6.67-6.70 (m, 2H),7.04 (d, J=8.40 Hz, 2H), 7.58 (dd, J=2.40, 8.80 Hz, 1H), 7.96 (d, J=8.80Hz, 1H), 8.12 (s, 1H), 8.20-8.23 (m, 1H), 8.28 (d, J=6.80 Hz, 1H), 8.49(s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.16 (d, J=2.00 Hz, 1H), 9.36 (s, 1H).Mol. wt.: 530.66. LC/MS: Retention time: 2.284 min. Purity: 98.7%.

Example 682-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(prop-2-yn-1-yl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.40 Hz, 6H), 3.15 (t, J=2.40 Hz,1H), 3.66-3.71 (m, 1H), 4.09 (dd, J=2.40, 5.60 Hz, 2H), 6.16 (s, 1H),7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.19 (s, 1H),8.35 (d, J=6.80 Hz, 1H), 8.50 (s, 1H), 8.70-8.72 (m, 2H), 9.16 (s, 1H),9.36 (s, 1H). Mol. wt.: 448.56. LC/MS: Retention time: 2.291 min.Purity: 98.1%.

Example 692-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3,3-dimethylbutyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.94 (s, 9H), 1.34 (d, J=6.40 Hz, 6H),1.47-1.51 (m, 2H), 3.66-3.71 (m, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.00,8.80 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.10 (s, 1H), 8.20 (t, J=6.00 Hz,1H), 8.34 (d, J=7.20 Hz, 1H), 8.49 (s, 1H), 8.72 (d, J=2.00 Hz, 1H),9.15 (s, 1H), 9.36 (s, 1H). Mol. wt.: 494.68. LC/MS: Retention time:2.866 min. Purity: 95.1%.

Example 702-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-isopentylthiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.91 (d, J=6.40 Hz, 6H), 1.33 (d, J=6.40 Hz,6H), 1.42-1.48 (m, 2H), 1.65-1.68 (m, 1H), 3.35 (2H, merged with waterpeak), 3.66-3.71 (m, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H),7.96 (d, J=8.80 Hz, 1H), 8.11 (s, 1H), 8.20-8.22 (m, 1H), 8.37 (bs, 1H),8.49 (s, 1H), 8.70 (bs, 1H), 9.16 (s, 1H), 9.38 (bs, 1H). Mol. wt.:480.65. LC/MS: Retention time: 2.826 min. Purity: 96.7%.

Example 712-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-propylthiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.92 (t, J=7.20 Hz, 3H), 1.33 (d, J=6.40 Hz,6H), 1.54-1.59 (m, 2H), 3.24-3.29 (m, 2H), 3.66-3.71 (m, 1H), 6.15 (s,1H), 7.58 (dd, J=2.40, 8.80 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.11 (s,1H), 8.25-8.26 (m, 1H), 8.35-8.37 (m, 1H), 8.36 (d, J=6.80 Hz, 1H), 8.49(s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.36 (s, 1H). Mol. wt.:452.6. LC/MS: Retention time: 2.49 min. Purity: 99.4%.

Example 722-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-pentylthiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.87-0.90 (m, 3H), 1.30-1.34 (m, 6H),1.53-1.57 (m, 2H), 3.29 (4H, merged with water peak), 3.68-3.73 (m, 1H),6.16 (s, 1H), 7.57 (dd, J=2.00, 8.80 Hz, 1H), 8.01 (dd, J=8.80, Hz, 1H),8.16 (s, 1H), 8.25-8.29 (m, 1H), 8.45 (s, 1H), 8.60 (bs, 1H), 9.22 (s,1H), 9.54 (bs, 1H). Mol. wt.: 480.65. LC/MS: Retention time: 2.864 min.Purity: 98.3%.

Example 732-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(cyclopropylmethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.25-0.29 (m, 2H), 0.43-0.48 (m, 2H),1.05-1.08 (m, 1H), 1.35 (d, J=6.00 Hz, 6H), 3.19 (t, J=6.40 Hz, 2H),3.67-3.72 (m, 1H), 6.16 (s, 1H), 7.59 (dd, J=2.00, 8.80 Hz, 1H), 7.96(d, J=8.80 Hz, 1H), 8.13 (s, 1H), 8.23 (t, J=6.00 Hz, 1H), 8.37 (d,J=6.80 Hz, 1H), 8.50 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.16 (s, 1H),9.37 (s, 1H). Mol. wt.: 464.61. LC/MS: Retention time: 2.531 min.Purity: 99.5%.

Example 742-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-chlorophenethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.28 (m, 6H), 2.90 (t, J=7.20 Hz, 2H),3.55-3.66 (m, 3H), 6.14 (s, 1H), 7.21-7.35 (m, 4H), 7.58 (dd, J=2.00,8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.12 (s, 1H), 8.25-8.32 (m, 2H),8.49 (s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.36 (s, 1H). Mol.wt.: 549.11. LC/MS: Retention time: 2.917 min. Purity: 99.5%.

Example 752-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-(thiophen-2-yl)ethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30 (d, J=6.40 Hz, 6H), 3.10 (t, J=6.80 Hz,2H), 3.56-3.61 (m, 2H), 3.67-3.68 (m, 1H), 6.15 (s, 1H), 6.93-6.97 (m,2H), 7.34 (dd, J=1.20, 5.00 Hz, 1H), 7.58 (dd, J=2.40, 8.80 Hz, 1H),7.98 (d, J=8.80 Hz, 1H), 8.16 (s, 1H), 8.38-8.41 (m, 2H), 8.47 (s, 1H),8.67 (bs, 1H), 9.18 (s, 1H), 9.42 (bs, 1H). Mol. wt.: 520.69. LC/MS:Retention time: 2.689 min. Purity: 94.5%.

Example 762-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-phenoxyethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.27-1.31 (m, 6H), 3.65-3.72 (m, 3H), 4.15(t, J=5.60 Hz, 2H), 6.14 (s, 1H), 6.93-6.97 (m, 3H), 7.28-7.32 (m, 2H),7.58 (dd, J=2.40, 9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.19 (s, 1H),8.36-8.38 (m, 2H), 8.49 (s, 1H), 8.70 (bs, 1H), 9.16 (s, 1H), 9.38 (bs,1H). Mol. wt.: 530.66. LC/MS: Retention time: 2.742 min. Purity: 97.8%.

Example 772-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(4-fluorophenethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.27 (m, 6H), 2.87 (t, J=7.20 Hz, 2H),3.52-3.58 (m, 2H), 3.63-3.68 (m, 1H), 6.14 (s, 1H), 7.10-7.14 (m, 2H),7.27-7.31 (m, 2H), 7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.95 (d, J=8.80 Hz,1H), 8.12 (s, 1H), 8.24-8.29 (m, 2H), 8.49 (s, 1H), 8.71 (d, J=2.40 Hz,1H), 9.15 (s, 1H), 9.36 (s, 1H). Mol. wt.: 532.66. LC/MS: Retentiontime: 2.76 min. Purity: 98.9%.

Example 782-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-(2-hydroxyethoxy)ethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.33 (d, J=6.00 Hz, 6H), 3.45-3.52 (m, 6H),3.57-3.59 (m, 2H), 3.66-3.70 (m, 1H), 4.59-4.61 (m, 1H), 6.15 (s, 1H),7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.82 (d, J=−100.40 Hz, 1H), 8.12-8.15(m, 2H), 8.33 (d, J=6.80 Hz, 1H), 8.50 (s, 1H), 8.71 (d, J=2.00 Hz, 1H),9.16 (s, 1H), 9.37 (s, 1H). Mol. wt.: 498.62. LC/MS: Retention time:1.888 min. Purity: 99.5%.

Example 792-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.40 Hz, 6H), 1.69-1.72 (m, 2H),3.35 (2H, merged with water peak), 3.49-3.52 (m, 2H), 3.68-3.69 (m, 1H),4.55 (s, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.40, 8.80 Hz, 1H), 7.96 (d,J=8.80 Hz, 1H), 8.12 (s, 1H), 8.25 (t, J=6.00 Hz, 1H), 8.33 (d, J=6.80Hz, 1H), 8.49 (s, 1H), 8.71 (d, J=2.40 Hz, 1H), 9.16 (s, 1H), 9.37 (s,1H). Mol. wt.: 468.6. LC/MS: Retention time: 1.916 min. Purity: 99.6%.

Example 802-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(4-hydroxybutyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.33 (d, J=6.40 Hz, 6H), 1.47-1.52 (m, 2H),1.55-1.60 (m, 2H), 3.41-3.45 (m, 2H), 3.66-3.71 (m, 1H), 4.40 (t, J=4.80Hz, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.96 (d, J=8.80Hz, 1H), 8.11 (s, 1H), 8.24 (t, J=5.60 Hz, 1H), 8.35 (d, J=6.80 Hz, 1H),8.49 (s, 1H), 8.72 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.36 (s, 1H). Mol.wt.: 482.62. LC/MS: Retention time: 1.961 min. Purity: 99.6%.

Example 81(R)-2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-hydroxy-2-phenylethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.31-1.35 (m, 6H), 3.38-3.43 (m, 1H),3.60-3.72 (m, 2H), 4.80-4.81 (m, 1H), 5.67 (d, J=4.40 Hz, 1H), 6.16 (s,1H), 7.24-7.28 (m, 1H), 7.33-7.37 (m, 2H), 7.40-7.42 (m, 2H), 7.58 (dd,J=2.00, 9.00 Hz, 1H), 7.95-7.99 (m, 2H), 8.16 (s, 1H), 8.25 (d, J=6.80Hz, 1H), 8.50 (s, 1H), 8.71 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.38 (s,1H). Mol. wt.: 530.66. LC/MS: Retention time: 2.392 min. Purity: 99.1%.

Example 822-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.40 Hz, 6H), 1.69-1.73 (m, 6H),2.50 (4H, merged with DMSO-d₆ peak), 3.35 (4H, merged with water peak),3.66-3.71 (m, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.96(d, J=8.80 Hz, 1H), 8.11 (s, 1H), 8.32-8.34 (m, 2H), 8.49 (s, 1H), 8.72(d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.36 (s, 1H). Mol. wt.: 521.7. LC/MS:Retention time: 2.24 min. Purity: 94.6%.

Example 832-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-(piperidin-1-yl)propyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.33-1.39 (m, 8H), 1.45-1.51 (m, 4H),1.68-1.73 (m, 2H), 2.29-2.34 (m, 5H), 2.52 (2H, merged with DMSO-d₆peak), 3.66-3.71 (m, 1H), 6.15 (s, 1H), 7.58 (dd, J=2.40, 9.00 Hz, 1H),7.96 (d, J=8.80 Hz, 1H), 8.11 (s, 1H), 8.27 (t, J=5.60 Hz, 1H), 8.33 (d,J=6.80 Hz, 1H), 8.49 (s, 1H), 8.72 (d, J=2.40 Hz, 1H), 9.15 (s, 1H),9.36 (s, 1H). Mol. wt.: 535.73. LC/MS: Retention time: 2.402 min.Purity: 96.7%.

Example 842-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-cyclohexylethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.89-0.95 (m, 2H), 1.12-1.19 (m, 3H), 1.34(d, J=6.00 Hz, 6H), 1.43-1.48 (m, 2H), 1.61-1.75 (m, 5H), 1.99-2.01 (m,1H), 3.36 (2H, merged with water peak), 3.66-3.71 (m, 1H), 6.15 (s, 1H),7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.11 (s, 1H),8.20 (t, J=6.00 Hz, 1H), 8.37 (bs, 1H), 8.49 (s, 1H), 8.71 (bs, 1H),9.16 (s, 1H), 9.37 (bs, 1H). Mol. wt.: 520.7. LC/MS: Retention time:3.236 min. Purity: 98.2%.

Example 852-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-(pyridin-4-yl)ethyl)thiazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.26 (d, J=6.40 Hz, 6H), 2.92 (t, J=6.80 Hz,2H), 3.59-3.66 (m, 3H), 6.14 (s, 1H), 7.30 (d, J=5.60 Hz, 1H), 7.58 (dd,J=2.40, 9.00 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.13 (s, 1H), 8.25 (d,J=6.80 Hz, 1H), 8.36-8.39 (m, 1H), 8.47-8.49 (m, 3H), 8.71 (d, J=2.00Hz, 1H), 9.16 (s, 1H), 9.36 (s, 1H). Mol. wt.: 515.65. LC/MS: Retentiontime: 2.13 min. Purity: 99.7%.

Oxazoles

Synthesis of ethyl2-(6-chloro-4-(isopropylamino)nicotinamido)-3-oxobutanoate (27a): Astirred solution of 6-chloro-4-(isopropylamino)nicotinic acid (2) in DCM(15 mL) was cooled to 0° C., oxalyl chloride (2 equiv) was added,followed by addition of 2 drops of DMF. The reaction mixture was stirredat room temperature for 2 h. The reaction mixture was concentrated toremove excess of oxalyl chloride. The acyl chloride, generated in-situwas dissolved in THF and added dropwise to a cool, stirred solution ofethyl 2-amino-3-oxobutanoate (1.1 equiv.) and NMM (5 equiv.) in THF. Thereaction temperature was slowly brought to room temperature and stirredovernight. The reaction mixture was diluted with EtOAc and washed withwater, followed by brine solution. The EtOAc layer was collected, driedover Na₂SO₄, filtered and concentrated. The crude material obtained waspurified by column chromatography through silica gel and EtOAc: Pet.Ether as eluent to afford the title compound, ethyl2-(6-chloro-4-(isopropylamino)nicotinamido)-3-oxobutanoate.

Synthesis of ethyl2-(6-chloro-4-(isopropylamino)nicotinamido)-4-methyl-3-oxopentanoate(27b): Followed the same procedure as mentioned for the synthesis ofcompound no. 27a, using compound 26b, instead of compound, 26a.

Synthesis of ethyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate(28a): To a stirred solution of ethyl2-(6-chloro-4-(isopropylamino)nicotinamido)-3-oxobutanoate (27a) (200mg, 0.58 mmol) in DCM (10 mL), triphenyl phosphine (2 equiv.), iodine (2equiv.) and triethyl amine (3 equiv.) were added and stirred at roomtemperature for 4 h. The reaction mixture was diluted using DCM andwashed with water. The organic layer was collected, dried over Na₂SO₄,filtered and concentrated. The crude material obtained was purified bycolumn chromatography using silica gel and EtOAc: Pet. Ether as eluentto obtain the title compound, ethyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate.¹H NMR: 400 MHz, DMSO-d₆: δ 1.25 (d, J=6.40 Hz, 6H), 1.33 (t, J=7.20 Hz,3H), 2.67 (s, 3H), 3.90-3.95 (m, 1H), 4.31 (q, J=7.20 Hz, 2H), 6.89 (s,1H), 8.47 (d, J=7.60 Hz, 1H), 8.54 (s, 1H).

Synthesis of ethyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazole-4-carboxylate(28b): Followed the same procedure as mentioned for the synthesis ofcompound no. 28a, using respective starting material, compound no. 27b.

Example 86

Synthesis of ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate:Ethyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate(28a) (50 mg, 0.15 mmol) was dissolved in 1,4-Dioxane (5 mL): H₂O (1mL), to it benzo[d]thiazol-6-amine (0.15 mmol), Na₂CO₃ (0.6 mmol) andxanthphos (0.06 mmol) were added and degassed for 10 min. Pd₂(dba)₃(0.06 mmol) was added and degassed once again for 15 min and heated at115° C., overnight. The reaction mass was filtered through a small padof celite and concentrated the filtrate to remove solvent. The crudematerial obtained was purified by column chromatography through silicagel and MeOH: CHCl₃ as eluent. The material obtained was furtherpurified by preparative TLC to obtain the title compound, ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate.¹H NMR: 400 MHz, DMSO-d₆: δ 1.28-1.35 (m, 9H), 2.66 (s, 3H), 3.71-3.72(m, 1H), 4.30 (q, J=7.20 Hz, 2H), 6.16 (s, 1H), 7.59 (dd, J=2.40, 9.00Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.10 (d, J=7.20 Hz, 1H), 8.53 (s, 1H),8.66 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.36 (s, 1H). LC/MS: AscentisExpress C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mMNH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min; retention time: 2.127 min; LCMS (ES-API), m/z 438.2 (M+H).HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O:0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retentiontime: 7.483 min; Purity: 99.7%.

Synthesis of ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazole-4-carboxylate(29): Followed the same procedure as mentioned for the synthesis ofExample 86, using respective starting material, compound no. 28b.

TABLE 4

Example No. R R₁ 87 CH₃ NH₂ 88 i-Pr

89 i-Pr

Example 87

Synthesis of2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamide:A solution of ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate(Example 86) (30 mg, 0.06 mmol) in MeOH (4 mL) was cooled to 0° C., NH₃(g) was purged for 5 min. The reaction mixture was heated at 80° C. in aclosed condition for 48 h. The reaction mixture was cooled andtransferred to rbf, concentrated to get solid material. The crudematerial obtained was purified by prep HPLC to furnish the desiredcompound,2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamide.¹H NMR: 400 MHz, DMSO-d₆: δ 1.33 (d, J=6.40 Hz, 6H), 2.63 (s, 1H),3.68-3.73 (m, 1H), 6.16 (s, 1H), 7.49 (bs, 1H), 7.59 (dd, J=2.40, 9.00Hz, 1H), 7.75 (d, J=7.20 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.52 (s, 1H),8.66 (d, J=2.00 Hz, 1H), 9.14 (s, 1H), 9.32 (s, 1H). LC/MS:(Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H₂O: 20 mMNH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient 0-100% Bover 1.5 min (3.2 min run time); retention time: 1.687 min; LCMS(ES-API), m/z 409.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 12 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 5.651 min; Purity: 99.9%.

Example 88

Synthesis of2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazol-4-yl)propan-2-ol:To a solution ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate(29) (150 mg, 0.34 mmol) in dry Tetrahydrofuran (10 mL) was added methylmagnesium bromide (2.132 mmol) (3.0 M in diethyl ether) at −78° C.Reaction mixture was allowed to warm up to 25° C. over 2 h. The reactionmixture was cooled to 0° C. and quenched by the addition of saturatedaqueous NH₄Cl solution dropwise. Extracted with ethyl acetate, driedover Na₂SO₄, filtered and concentrated to get the crude product, whichwas purified by flash column using ethyl acetate/hexanes as eluent tofurnish2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazol-4-yl)propan-2-ol.¹H NMR: 400 MHz, DMSO-d₆: δ 1.26-1.27 (m, 13H), 1.48 (s, 6H), 3.63-3.71(m, 2H), 5.06 (s, 1H), 6.13 (s, 1H), 7.57 (dd, J=2.00, 8.80 Hz, 1H),7.95 (d, J=8.80 Hz, 1H), 8.28 (d, J=6.80 Hz, 1H), 8.51 (s, 1H), 8.75 (d,J=2.00 Hz, 1H), 9.15 (s, 1H), 9.28 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH:10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time);retention time: 1.842 min; LCMS (ES-API), m/z 452.2 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:7.608 min; Purity: 97.8%.

Example 89

Synthesis of(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazol-4-yl)methanol:To a solution of ethyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylate(29) (150 mg, 0.34 mmol) in dry Tetrahydrofuran (10 mL) was added LAH(0.739 mmol) (4% in THF) at −10° C. The reaction mixture was stirred at0° C. for 30 min, reaction temperature was then brought to roomtemperature and stirred for 30 min. The reaction mixture was cooled to0° C. and quenched by using ice flakes (until the H₂ gas evolutionceased), followed by 1N NaOH solution, filtered through celite,precipitate was washed with ethyl acetate. The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated in vacuum to givecrude compound. The crude material was purified by flash columnchromatography using silica gel and ethyl acetate/hexane as eluent toprovide(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazol-4-yl)methanol.¹H NMR: 400 MHz, DMSO-d₆: δ 1.28-1.30 (m, 12H), 3.68-3.73 (m, 1H),4.38-4.39 (m, 2H), 5.03-5.03 (m, 1H), 6.15 (s, 1H), 7.57 (dd, J=2.00,8.80 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.11 (d, J=6.80 Hz, 1H), 8.54 (s,1H), 8.74 (d, J=1.60 Hz, 1H), 9.15 (s, 1H), 9.30 (s, 1H). LC/MS: ZORBAXSB C18, 4.6×50 mm, 50 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA;Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3min run time); retention time: 1.703 min; LCMS (ES-API), m/z 424.0(M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH'² 2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 6.663 min; Purity: 99.2%.

Synthesis of2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylicacid (30a) and2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazole-4-carboxylicacid (30b): Followed the same procedure as mentioned in the synthesis ofcompound no. 9. LC/MS: Ascentis Express C18, 5×2.1 mm, 2.70 □μm; SolventA=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mMNH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.492 min; LCMS(ES-API), m/z 296.2 (M+H).

Synthesis of2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide(31):2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylicacid (30a) (100 mg, 0.338 mmol) was dissolved in DMF (5 mL).3-aminopropan-1-ol (1.691 mmol, 5 equiv.) and DIPEA (1.353 mmol, 4equiv.) were added to the reaction mixture and stirred at roomtemperature. HATU (1.014 mmol, 3 equiv.) was added to the reactionmixture and stirred for 3 h. The reaction mixture was concentrated underreduced pressure to remove excess of DMF. The residue obtained waspartitioned between water and EtOAc. The organic layer was separated,dried over Na₂SO₄, filtered and concentrated. The crude materialobtained was purified by flash column chromatography through silica geland MeOH: CHCl₃ as eluent to afford the title compound,2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide(31).

Example 90

Synthesis of2-(6-(benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide:To a stirred solution of(2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide(31) (100 mg, 0.283 mmol) in 1,4-Dioxane (10 mL),benzo[c][1,2,5]thiadiazol-5-amine (0.283 mmol, 1 equiv.), Na₂CO₃ (1.134mmol, 4 equiv.) and Xanthphos (0.113 mmol, 0.4 equiv.) were added anddegassed for 10 min. Pd₂(dba)₃ (0.113 mmol, 0.4 equiv.) was added anddegassed once again for 10 min. Heated the reaction mixture at 115° C.for overnight. The reaction was cooled and filtered through small pad ofcelite. The filtrate obtained was concentrated to provide crudematerial. The crude material was purified by column chromatographythrough silica gel and MeOH: CHCl₃ as eluent to afford2-(6-(benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide[Example 90]. ¹H NMR: 400 MHz, CD₃OD: δ 1.42 (d, J=6.40 Hz, 6H),1.83-1.84 (m, 2H), 2.71 (s, 3H), 3.51 (t, J=1.20 Hz, 2H), 3.72 (t,J=7.20 Hz, 2H), 3.81-3.83 (m, 1H), 6.28 (s, 1H), 7.67 (dd, J=2.00, 9.40Hz, 1H), 7.89 (dd, J=9.60, 9.20 Hz, 1H), 8.47 (s, 1H), 8.64 (s, 1H).LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 □μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 3 min; retention time: 1.896 min; LCMS (ES-API), m/z 466.0(M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 6.335 min; Purity: 98.7%.

Synthesis of Examples 91-105: The Examples in Table 5 were preparedaccording to the general method outlined for Example 90, usingappropriate amines and their respective starting materials.

TABLE 5

Compound No. R R₁ R₂ 90 CH₃

91 CH₃

92 CH₃

93 CH₃

94 CH₃

95 CH₃

96 CH₃

97 CH₃

98 CH₃

99 CH₃

100 CH₃

101 CH₃

102 CH₃

103 i-Pr

104 i-Pr

105 CH₃

Example 91(R)-(2-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)(3-hydroxypyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, CD₃OD: δ 1.37-1.37 (m, 7H), 2.09-2.10 (m, 2H), 2.69 (s,3H), 3.68-3.70 (m, 3H), 4.05-4.07 (m, 1H), 4.15-4.17 (m, 1H), 4.50-4.51(m, 1H), 6.29 (s, 1H), 7.68 (dd, J=2.00, 9.40 Hz, 1H), 7.88 (d, J=9.20Hz, 1H), 8.00-8.02 (m, 1H), 4.49 (bs, 1H), 8.65 (s, 1H). LC/MS: AscentisExpress C18, 5×2.1 mm-2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH;Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 3 min;retention time: 1.853 min; LCMS (ES-API), m/z 478.0 (M−H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:6.104 min; Purity: 96.6%.

Example 922-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-fluoro-3-hydroxypropyl)-5-methyloxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.36 (d, J=6.40 Hz, 6H), 2.65 (s, 3H),3.52-3.54 (m, 5H), 4.59-4.60 (m, 1H), 5.05 (t, J=5.60 Hz, 1H), 6.29 (s,1H), 7.70 (dd, J=2.40, 9.40 Hz, 1H), 7.82 (d, J=7.20 Hz, 1H), 7.95 (d,J=9.20 Hz, 1H), 8.16 (t, J=6.00 Hz, 1H), 8.62 (s, 1H), 8.76 (s, 1H),9.64 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2%ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 3 min; retention time: 1.920 min; LCMS (ES-API),m/z 486.2 (M+H). HPLC: XBridge (150×4.6 mm), 3.5 micron; Solvent A=5%ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFApH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0μL/min; Retention time: 7.057 min; Purity: 97.7%.

Example 932-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-5-methyloxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.18 (s, 6H), 1.34 (d, J=6.40 Hz, 6H), 2.64(s, 3H), 3.68-3.73 (m, 2H), 4.31-4.45 (m, 1H), 4.89 (s, 1H), 6.17 (s,1H), 7.59 (dd, J=2.00, 9.00 Hz, 1H), 7.75 (d, J=7.60 Hz, 1H), 7.96 (d,J=8.80 Hz, 1H), 8.13 (t, J=5.60 Hz, 1H), 8.53 (s, 1H), 8.66 (d, J=2.00Hz, 1H), 9.34 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.809 min;LCMS (ES-API), m/z 513.4 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 5.982 min; Purity: 95.2%.

Example 942-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(1-hydroxypropan-2-yl)-5-methyloxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.18 (s, 6H), 1.34 (d, J=6.40 Hz, 6H), 2.64(s, 3H), 3.41-3.46 (m, 1H), 3.68-3.73 (m, 2H), 4.30-4.45 (m, 1H), 4.89(s, 1H), 6.17 (s, 1H), 7.59 (dd, J=2.00, 8.80 Hz, 1H), 7.75 (d, J=7.20Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.12 (t, J=5.60 Hz, 1H), 8.32 (s, 1H),8.53 (s, 1H), 8.66 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.34 (s, 1H).LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O:0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over2 min (3 min run time); retention time: 1.61 min; LCMS (ES-API), m/z467.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5%ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFApH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0μL/min; Retention time: 5.892 min; Purity: 92.1%.

Example 95 Ethyl2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamido)propanoate

¹H NMR: 400 MHz, DMSO-d₆: δ 1.35-1.36 (m, 6H), 1.43-1.45 (m, 3H), 2.64(s, 3H), 4.14-4.17 (m, 2H), 4.45-4.49 (m, 1H), 6.18 (s, 1H), 7.60 (dd,J=2.40, 8.80 Hz, 1H), 7.86 (d, J=6.40 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H),8.26 (d, J=7.60 Hz, 1H), 8.54 (s, 1H), 8.67 (d, J=2.40 Hz, 1H), 9.16 (s,1H), 9.36 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.943 min;LCMS (ES-API), m/z 509.4 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 7.044 min; Purity: 93.2%.

Example 962-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-hydroxy-2-methylpropyl)-5-methyloxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.14 (s, 6H), 1.32 (d, J=6.40 Hz, 1H), 2.64(s, 3H), 2.74 (d, J=4.80 Hz, 1H), 2.81 (d, J=4.80 Hz, 1H), 3.23 (3H,merged with water peak), 3.70-3.73 (m, 1H), 4.69 (s, 1H), 6.17 (s, 1H),7.57-7.61 (m, 2H), 7.84 (d, J=6.80 Hz, 1H), 7.96 (d, J=8.40 Hz, 1H),8.27 (s, 1H), 8.54 (s, 1H), 8.67 (d, J=2.40 Hz, 1H), 9.16 (s, 1H), 9.36(s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2%ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min; retention time: 1.927 min; LCMS(ES-API), m/z 481.2 (M+H). HPLC: XBridge (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.568 min; Purity: 92.8%.

Example 97(2-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)(3-hydroxypiperidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.31-1.32 (m, 6H), 1.46 (bs, 2H), 1.76-1.89(m, 5H), 2.84 (2H, merged with water peak), 3.55 (bs, 1H), 3.74-3.75 (m,1H), 4.15-4.18 (m, 2H), 4.81-4.96 (m, 1H), 6.29 (s, 1H), 7.70 (dd,J=2.00, 9.60 Hz, 1H), 7.81 (bs, 1H), 7.95 (d, J=9.60 Hz, 1H), 8.63 (s,1H), 8.77 (d, J=1.60 Hz, 1H), 9.65 (s, 1H). LC/MS: Ascentis Express C18,5×2.1 mm, 2.70 □μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; SolventB=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min;retention time: 1.916 min; LCMS (ES-API), m/z 494.2 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:6.398 min; Purity: 97.4%.

Example 982-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyl-N-(tetrahydro-2H-pyran-4-yl)oxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.37 (d, J=6.40 Hz, 6H), 1.62-1.68 (m, 2H),1.79-1.81 (m, 2H), 2.65 (s, 3H), 3.39-3.45 (2H, merged with water peak),3.72-3.75 (m, 1H), 3.87-3.90 (m, 2H), 3.99-4.00 (m, 1H), 6.28 (s, 1H),7.70 (dd, J=1.60, 9.40 Hz, 1H), 7.85 (d, J=7.60 Hz, 1H), 7.94-7.97 (m,2H), 8.62 (s, 1H), 8.77 (d, J=1.60 Hz, 1H), 9.64 (s, 1H). LC/MS:Ascentis Express C18, 5×2.1 mm, 2.70 □μm; Solvent A=2% ACN: 98% H₂O: 10mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min; retention time: 1.924 min; LCMS (ES-API), m/z 494.2 (M+H).HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O:0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retentiontime: 7.082 min; Purity: 96.8%.

Example 992-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(4-hydroxycyclohexyl)-5-methyloxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.31 (m, 4H), 1.35 (d, J=6.40 Hz, 6H),1.76-1.88 (m, 4H), 2.64 (s, 3H), 3.69-3.73 (m, 2H), 4.55-4.57 (m, 1H),6.28 (s, 1H), 7.65-7.72 (m, 2H), 7.93-7.96 (m, 2H), 8.61 (s, 1H), 8.76(d, J=1.60 Hz, 1H), 9.64 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm,2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2%H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min; retention time:1.938 min; LCMS (ES-API), m/z 508.2 (M+H). HPLC: Sunfire C18 (150×4.6mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; SolventB=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23min run time); Flow rate: 1.0 μL/min; Retention time: 6.653 min; Purity:95.5%.

Example 1002-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(2-hydroxyethyl)-5-methyloxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.36 (d, J=6.40 Hz, 6H), 2.65 (s, 3H), 3.36(2H, merged with water peak), 3.52-3.56 (m, 2H), 3.73-3.75 (m, 1H), 4.82(t, J=5.20 Hz, 1H), 6.29 (s, 1H), 7.70 (dd, J=2.00, 9.60 Hz, 1H),7.83-7.90 (m, 2H), 7.95 (d, J=9.20 Hz, 1H), 8.32 (s, 1H), 8.62 (s, 1H),8.76 (d, J=2.00 Hz, 1H), 9.64 (s, 1H). LC/MS: Ascentis Express C18,5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; SolventB=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min;retention time: 1.868 min; LCMS (ES-API), m/z 454.2 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:5.748 min; Purity: 98.4%.

Example 1012-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-methyloxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.40 Hz, 6H), 1.68-1.71 (m, 2H),2.64 (s, 3H), 3.32-3.39 (m, 2H), 3.52-3.55 (m, 2H), 3.70-3.73 (m, 1H),4.59-4.62 (m, 1H), 6.17 (s, 1H), 7.60 (dd, J=2.00, 8.80 Hz, 1H), 7.75(d, J=6.80 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.05 (s, 1H), 8.53 (s, 1H),8.67 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.34 (s, 1H). LC/MS: AscentisExpress C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mMNH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min; retention time: 1.772 min; LCMS (ES-API), m/z 467.2 (M+H).HPLC: XBridge Phenyl (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 6.342 min; Purity: 91.4%.

Example 102(R)-(2-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)(3-hydroxypyrrolidin-1-yl)methanone

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.31 (m, 6H), 1.81-1.95 (m, 2H), 2.62(s, 3H), 3.41-4.10 (m, 6H), 4.32-4.35 (m, 1H), 7.59 (dd, J=2.00, 8.80Hz, 1H), 7.85 (dd, J=7.20, 15.20 Hz, 1H), 7.96 (d, J=9.20 Hz, 1H), 8.32(s, 1H), 8.54 (s, 1H), 8.67 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.35 (s,1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.70 □μm; Solvent A=2% ACN:98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min; retention time: 1.728 min; LCMS(ES-API), m/z 479.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 5.704 min; Purity: 98.1%.

Example 1032-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-isopropyloxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30-1.36 (m, 12H), 3.72-3.77 (m, 1H),3.82-3.89 (m, 1H), 6.28 (s, 1H), 7.52 (bs, 1H), 7.62 (bs, 1H), 7.71 (dd,J=2.00, 9.60 Hz, 1H), 7.78 (d, J=7.20 Hz, 1H), 7.96 (d, J=9.60 Hz, 1H),8.68 (s, 1H), 8.80 (d, J=1.60 Hz, 1H), 9.63 (s, 1H). LC/MS: AscentisExpress C18, 5×2.1 mm-2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH;Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 3 min;retention time: 2.051 min; LCMS (ES-API), m/z 436.2 (M−H). HPLC: XBridge(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.876 min;Purity: 96.5%.

Example 1042-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-5-isopropyloxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30-1.36 (m, 12H), 1.67-1.73 (m, 2H),3.31-3.41 (m, 3H), 3.51-3.55 (m, 2H), 3.71-3.76 (m, 1H), 3.81-3.88 (m,1H), 4.59-4.62 (m, 1H), 6.28 (s, 1H), 7.70 (dd, J=2.40, 9.40 Hz, 1H),7.78 (d, J=7.20 Hz, 1H), 7.95 (d, J=9.20 Hz, 1H), 8.07 (t, J=5.60 Hz,1H), 8.32 (s, 1H), 8.68 (s, 1H), 8.79 (d, J=2.00 Hz, 1H), 9.64 (s, 1H).LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 1.5 min; retention time: 1.938 min; LCMS (ES-API), m/z496.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5%ACN: 95% H₂O: 0.05% TFA pH'² 2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFApH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0μL/min; Retention time: 7.134 min; Purity: 98.3%.

Example 105 Synthesis ofN-(2-aminoethyl)-2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamide

Step A: tert-butyl(2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamido)ethyl)carbamatewas prepared by following the same procedure as mentioned in thesynthesis of compound no. 3, using tert-butyl(2-(2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamido)ethyl)carbamateas the starting material.

Step B: A solution of tert-butyl(2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamido)ethyl)carbamatein DCM (5 mL) was treated with ether.HCl (5 mL) at 0° C. The reactionmixture was stirred at 0° C. for 30 min. The reaction temperature wasraised to room temperature and stirred for 30 min. The reaction mixturewas concentrated to dryness. The material obtained was purified by prep.HPLC to affordN-(2-aminoethyl)-2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxamide¹H NMR: 400 MHz, DMSO-d₆: δ 1.35 (d, J=6.40 Hz, 6H), 2.64 (s, 3H),2.70-2.80 (m, 2H), 3.70-3.74 (m, 1H), 6.17 (s, 1H), 7.60 (dd, J=2.00,9.00 Hz, 1H), 7.79 (d, J=7.20 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.02(bs, 1H), 8.53 (s, 1H), 8.67 (d, J=2.00 Hz, 1H), 9.16 (s, 1H), 9.35 (s,1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN:98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min; retention time: 1.646 min; LCMS(ES-API), m/z 452.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flowrate: 1.0 μL/min; Retention time: 8.956 min; Purity: 91.1%.

Synthesis of2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carbonylazide (33):2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylicacid (30a) (750 mg, 2.54 mmol) and thionyl chloride (12.68 mmol) wererefluxed at 100° C. for 20 h. Thionyl chloride was removed under reducedpressure. The resulting solid acid chloride was dissolved in acetone (15mL) and cooled to 0° C. Sodium azide (7.61 mmol) dissolved in water (3mL) was added to the reaction mixture at 0° C. and stirred for 30 min.The reaction temperature was raised to room temperature and stirred for5 h. The reaction mixture was concentrated to remove the solvent. Thecompound precipitated in the aqueous layer was filtered and dried undervacuum to obtain the desired compound2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carbonylazide. LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90%H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% Bover 2 min (3 min run time); retention time: 2.363 min.

Synthesis of tert-butyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-ylcarbamate(34): A solution of2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carbonylazide (33) (500 mg, 1.559 mmol) in chloroform (15 mL) was refluxed for10 h. t-Butanol (0.5 mL, 4.68 mmol) was added and once again refluxedfor 10 h. The reaction mixture was concentrated and purified by flashcolumn chromatography using silica gel and EtOAC: pet ether as elutingagents to afford tert-butyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-ylcarbamate.LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 1.5 min; retention time: 2.086 min; LCMS (ES-API), m/z367.2 (M+H).

Example 106

Synthesis of tert-butyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-ylcarbamate:Followed the same procedure as mentioned in the synthesis of compoundno. 3 using respective starting materials. ¹H NMR: 400 MHz, DMSO-d₆: δ1.28 (d, J=6.40 Hz, 6H), 1.46 (s, 9H), 2.28 (s, 3H), 3.67-3.72 (m, 1H),6.14 (s, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.91-7.96 (m, 2H), 8.47(s, 1H), 8.67 (d, J=2.00 Hz, 1H), 8.88 (bs, 1H), 9.15 (s, 1H), 9.29 (s,1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN:98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min; retention time: 2.101 min; LCMS(ES-API), m/z 481.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 7.712 min; Purity: 96.5%.

Synthesis of tert-butylacetyl(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)carbamate(35): A solution of tert-butyl2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-ylcarbamate(Example 106) (20 mg, 0.042 mmol) in Tetrahydrofuran (5 mL) was cooledto 0° C. and treated with NaH (0.042 mmol). Stirred the reaction mixtureat 0° C. for 10 min. Added Ac₂O (0.042 mmol) to the reaction mixture andstirred at 0° C. for 0.5 h. The reaction mixture was quenched with icepieces and extracted with ethyl acetate. The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated to affordtert-butylacetyl(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)carbamate.LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.90 min; LCMS (ES-API), m/z 523.6 (M+H).

Example 107

Synthesis ofN-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)acetamide:A solution of tert-butylacetyl(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)carbamate(35) (30 mg, 0.057 mmol) in DCM (5 mL) was treated with TFA (0.230 mmol)and stirred at room temperature for 3 h. The reaction mixture wasconcentrated and azeotroped with chloroform three times to obtain gummysolid. The crude material obtained was purified by prep HPLC to furnishN-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-5-methyloxazol-4-yl)acetamide.¹H NMR: 400 MHz, CD₃OD: δ 1.33 (d, J=6.40 Hz, 6H), 2.16 (s, 3H), 2.35(s, 3H), 3.73-3.79 (m, 1H), 6.14 (s, 1H), 7.52 (dd, J=2.40, 8.80 Hz,1H), 7.97 (d, J=8.80 Hz, 1H), 8.38 (d, J=2.00 Hz, 1H), 8.49 (s, 1H),9.07 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; SolventA=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mMNH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.823 min; LCMS(ES-API), m/z 423.2 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 6.484 min; Purity: 95.1%.

Synthesis of methyl2-(6-chloro-4-(isopropylamino)nicotinamido)-3-hydroxypropanoate (36): Toa stirred solution of 6-chloro-4-(isopropylamino)nicotinic acid (9) (1.3g, 6.06 mmol) in DMF (25 mL), methyl 2-amino-3-hydroxypropanoate (12.11mmol) and DIPEA (18.17 mmol) were added followed by the addition of HATU(30.3 mmol) to the reaction mixture and stirred at room temperature for2 h. DMF was removed under reduced pressure. The residue obtained wasdiluted with EtOAC and washed with water and 10% NaHCO₃ solution. Theorganic layer was collected, dried over Na₂SO₄, filtered andconcentrated. The crude material obtained was purified by flashchromatography using silica gel and EtOAC: pet ether as eluent to affordthe title compound, methyl2-(6-chloro-4-(isopropylamino)nicotinamido)-3-hydroxypropanoate. LC/MS:ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA;Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3min run time); retention time: 1.312 min; LCMS (ES-API), m/z 316.0(M+H).

Synthesis of methyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylate(37): To a stirred solution of methyl2-(6-chloro-4-(isopropylamino)nicotinamido)-3-hydroxypropanoate (36)(100 mg, 0.317 mmol) in DCM (15 mL), DAST (0.317 mmol) was added at −78°C. and stirred for 4 h. K₂CO₃ (0.633 mmol) was added to the reactionmixture and stirred for 3 h. The reaction mixture was diluted with DCMand washed with water (twice) followed by brine solution. The organiclayer was collected, dried over Na₂SO₄, filtered and concentrated. Thecrude material obtained was purified by flash chromatography usingsilica gel and EtOAC: pet ether as eluent to afford the title compound,methyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylate.¹H NMR: 400 MHz, DMSO-d₆: δ 1.20-1.21 (m, 6H), 3.73 (s, 3H), 3.84-3.89(m, 1H), 4.51-4.59 (m, 2H), 5.07-5.12 (m, 1H), 6.83 (s, 1H), 8.36 (s,1H), 8.80 (d, J=7.60 Hz, 1H).

Synthesis of ethyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)oxazole-4-carboxylate (38):To a stirred solution of methyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylate(37) (100 mg, 0.336 mmol) in DCM (20 mL), DBU (1.008 mmol) andbromotrichloromethane (0.403 mmol) were added at 0° C. and stirred thereaction mixture for 2 h at 0° C. Reaction temperature was raised toroom temperature and stirred the reaction for 10 min. The reactionmixture was diluted with DCM and washed with water, 10% NaHCO₃ solutionand brine solution. The organic layer was collected, dried over Na₂SO₄,filtered and concentrated. The crude material obtained was purified byflash chromatography using silica gel and EtOAC: pet ether as eluent toafford the title compound, ethyl2-(6-chloro-4-(isopropylamino)pyridin-3-yl)oxazole-4-carboxylate (38).¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.27 (m, 6H), 3.87 (s, 3H), 3.92-3.97(m, 1H), 6.92 (s, 1H), 8.36 (d, J=7.60 Hz, 1H), 8.60 (s, 1H), 9.00 (s,1H).

Synthesis of2-(6-chloro-4-(isopropylamino)pyridin-3-yl)oxazole-4-carboxylic acid(39): Followed the same procedure as mentioned in the synthesis ofcompound no. 9. LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; SolventA=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mMNH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.473 min; LCMS(ES-API), m/z 282.2 (M+H).

[2-(6-Chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-(piperidin-1-yl)propyl)oxazole-4-carboxamide(40b)]: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 1.5 min; retention time: 1.622 min; LCMS (ES-API), m/z406.2 (M+H).

Synthesis of Examples 108-110: Followed the same procedure as mentionedfor compound no. 13, using appropriate amines and their respectivestarting materials.

TABLE 6

Example No. R 108 NH₂ 109

110

Example 1082-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)oxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.40 Hz, 6H), 3.70-3.74 (m, 1H),6.17 (s, 1H), 7.60 (dd, J=2.00, 8.80 Hz, 1H), 7.75 (bs, 1H), 7.83 (d,J=7.20 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.56-8.56 (m, 2H), 8.67 (d,J=2.00 Hz, 1H), 9.16 (s, 1H), 9.35 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH:10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time);retention time: 1.43 min; LCMS (ES-API), m/z 395.0 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:5.34 min; Purity: 96.8%.

Example 1092-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-(piperidin-1-yl)propyl)oxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.31-1.40 (m, 6H), 1.61-1.72 (m, 3H),1.81-1.85 (m, 2H), 1.92-1.97 (m, 2H), 2.84-2.92 (m, 2H), 3.07-3.12 (m,2H), 3.34-3.49 (4H, merged with water peak), 3.71-3.78 (m, 1H), 6.20 (s,1H), 7.59 (dd, J=2.00, 8.80 Hz, 1H), 8.01-8.03 (m, 1H), 8.45-8.56 (m,2H), 8.66 (s, 1H), 8.97 (bs, 1H), 9.23 (s, 1H), 9.58 (bs, 1H). LC/MS:ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA;Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3min run time); retention time: 1.322 min; LCMS (ES-API), m/z 520.2(M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min;Retention time: 9.410 min; Purity: 97.6%.

Example 1102-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-(3-(pyrrolidin-1-yl)propyl)oxazole-4-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.35 (d, J=6.40 Hz, 6H), 1.68-1.76 (m, 6H),1.85-1.89 (m, 4H), 2.42-2.47 (m, 6H), 3.69-3.74 (m, 1H), 6.17 (s, 1H),7.60 (dd, J=2.00, 8.80 Hz, 1H), 7.84 (d, J=7.20 Hz, 1H), 7.96 (d, J=8.80Hz, 1H), 8.22 (t, J=6.00 Hz, 1H), 8.56 (d, J=0.80 Hz, 1H), 8.67 (d,J=2.00 Hz, 1H), 9.16 (s, 1H), 9.37 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH:10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time);retention time: 1.307 min; LCMS (ES-API), m/z 506.2 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time:9.117 min; Purity: 92.3%.

Oxadiazoles

Synthesis of5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-thiol(42): 6-chloro-4-(isopropylamino)nicotinohydrazide (10) (1.5 g, 8.7mmol) was taken in EtOH (10 mL): H₂O (5 mL). Added KOH (13 mmol, 1.5equiv.) followed by the addition of CS₂ (87 mmol, 10 equiv.) to thereaction mixture and heated at 90° C., overnight. The reaction mass wasconcentrated under reduced pressure to remove solvents from the reactionmixture. The crude material obtained was taken to next step as suchwithout purification. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm;Solvent A=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20mM NH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time);retention time: 1.27 min; LCMS (ES-API), m/z 269.0 (M−H).

Synthesis of2-chloro-N-isopropyl-5-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyridin-4-amine(43): Methyl iodide (22 mmol, 2 equiv.) was added to a solution of5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-thiol(42) (1.5 g, 5.5 mmol) in MeOH (10 mL). The reaction mixture was stirredovernight at room temperature. The reaction mass was concentrated underreduced pressure. The crude material obtained was purified by columnchromatography through silica gel and MeOH: DCM as eluent to furnish thedesired compound,2-chloro-N-isopropyl-5-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyridin-4-amine(43). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90%H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient0-100% B over 1.5 min (3.2 min run time); retention time: 1.994 min;LCMS (ES-API), m/z 285.1 (M+H).

Synthesis of2-chloro-N-isopropyl-5-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)pyridin-4-amine(44): m-CPBA (4 mmol, 3 equiv.) was added to a stirred solution of2-chloro-N-isopropyl-5-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyridin-4-amine(43) (500 mg, 1.4 mmol) in DCM (5 mL). The reaction mixture was stirredovernight at room temperature. The reaction mass was diluted using DCM.The DCM layer was washed with saturated solution of NaHCO₃. Collectedthe DCM layer, dried over Na₂SO₄, filtered and concentrated. The crudematerial contained sulfone as well as sulfoxide compounds. The twocompounds were separated by column chromatography through silica gel andMeOH: DCM as eluent. LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.805 min;LCMS (ES-API), m/z 316.8 (M+H).

Synthesis of tert-butyl4-((5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate(45): tert-butyl 4-aminopiperidine-1-carboxylate (8 mmol, 5 equiv.) wasadded to a stirred solution of2-chloro-N-isopropyl-5-(5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl)pyridin-4-amine(44) (500 mg, 1.7 mmol) in Dioxan (5 mL) and heated at 90° C. for 4 h.The reaction mass was concentrated under reduced pressure. The crudematerial obtained was purified by column chromatography through silicagel and MeOH: DCM as eluent to afford the desired compound, tert-butyl4-((5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate.LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H₂O:20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient0-100% B over 1.5 min (3.2 min run time); retention time: 2.049 min;LCMS (ES-API), m/z 437.2 (M+H).

Example 111

Synthesis of tert-butyl4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate:To a solution of tert-butyl4-((5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate(45) (400 mg, 0.9 mmol) in dioxane (10 mL): H₂O (2 mL), 6-aminobenzothiazole (1.3 mmol, 1.5 equiv.), xanthphos (0.4 mmol, 0.5 equiv.)and Na₂CO₃ (2.7 mmol, 3 equiv.) were added and degassed for 10 min. Tothe reaction mixture Pd₂(dba)₃ (0.4 mmol, 0.5 equiv.) was added anddegassed again for 10 min. It was then heated at 110° C. for overnight.The reaction mass was cooled and filtered through small pad of celite.The filtrate obtained was concentrated to provide crude material. Thecrude material was purified by column chromatography through silica geland MeOH: DCM as eluent. The material obtained was further purified byprep. HPLC to afford tert-butyl4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate.¹H NMR: 400 MHz, CD₃OD: δ 1.34 (d, J=6.00 Hz, 6H), 1.48 (s, 9H),1.58-1.60 (m, 2H), 1.96-2.06 (m, 4H), 3.29-3.34 (2H, merged with thewater peak), 3.61-3.64 (m, 1H), 3.78-3.82 (m, 1H), 4.00-4.04 (m, 2H),6.16 (s, 1H), 7.53-7.58 (m, 2H), 7.97 (d, J=8.80 Hz, 1H), 8.37 (s, 1H),8.43 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: Purospher@star RP-18, 4×55mm, 3 m; Solvent A=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN:10% H₂O: 20 mM NH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min runtime); retention time: 2.028 min; LCMS (ES-API), m/z 551.2 (M+H). HPLC:Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05%TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100%B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:7.276 min; Purity: 98.8%.

Synthesis of Examples 112-130: Prepared according to the generalprocedure outlined for Example 111, using their respective startingmaterials and appropriate amine.

TABLE 7

Compound No. R R₁ 111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

Example 1123-((5-(6-(Benzo[c][1,2,5]thiadiazol-5-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)propan-1-ol

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30 (d, J=6.40 Hz, 6H), 1.73-1.76 (m, 2H),3.31 (1H, merged with water peak), 3.49-3.52 (m, 2H), 3.73-3.75 (m, 1H),4.46-4.53 (m, 1H), 6.29 (s, 1H), 7.59 (d, J=7.20 Hz, 1H), 7.70 (dd,J=2.00, 9.40 Hz, 1H), 7.78 (bs, 1H), 7.95 (d, J=9.20 Hz, 1H), 8.32 (s,1H), 8.38 (s, 1H), 8.77 (d, J=1.60 Hz, 1H), 9.64 (s, 1H). LC/MS:Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H₂O: 20 mMNH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient 0-100% Bover 1.5 min (3.2 min run time); retention time: 1.601 min; LCMS(ES-API), m/z 427.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH'² 2.5; Solvent B=95% ACN: 5%H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time);Flow rate: 1.0 μL/min; Retention time: 5.991 min; Purity: 93.1%.

Example 113(1-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-2-yl)methanol

¹H NMR: 400 MHz, CD₃OD: δ 1.34 (d, J=6.40 Hz, 6H), 1.96-2.20 (m, 5H),3.59-3.83 (m, 5H), 4.05-4.08 (m, 1H), 6.17 (s, 1H), 7.54 (dd, J=2.00,8.80 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.38 (s, 1H), 8.43 (d, J=2.00 Hz,1H), 9.08 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 m; SolventA=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mMNH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.628 min; LCMS (ES-API), m/z 452.2 (M+H). HPLC: XBridge Phenyl(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.722 min;Purity: 98.4%.

Example 1141-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)pyrrolidin-3-ol

¹H NMR: 400 MHz, CD₃OD: δ 1.34 (d, J=6.40 Hz, 6H), 2.12-2.26 (m, 2H),3.55-3.58 (m, 1H), 3.71-3.81 (m, 5H), 4.59 (bs, 1H), 6.17 (s, 1H), 7.54(dd, J=2.40, 8.80 Hz, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.37 (s, 1H), 8.42(d, J=2.40 Hz, 1H), 9.08 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm,3 m; Solvent A=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10%H₂O: 20 mM NH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time);retention time: 1.499 min; LCMS (ES-API), m/z 436.2 (M−H). HPLC: XBridgePhenyl (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:6.216 min; Purity: 98.1%.

Example 115(R)-4-((5-(5-((2-Fluoro-3-hydroxypropyl)amino)-1,3,4-oxadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile

¹H NMR: 400 MHz, CD₃OD: δ 1.35 (d, J=6.40 Hz, 6H), 3.60-3.86 (m, 5H),4.70-4.80 (m, 1H), 6.20 (s, 1H), 7.60 (d, J=11.20 Hz, 2H), 7.74 (d,J=8.80 Hz, 2H), 8.38 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 m;Solvent A=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20mM NH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time);retention time: 1.582 min; LCMS (ES-API), m/z 410.2 (M−H). HPLC: XBridgePhenyl (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 L/min; Retention time:6.648 min; Purity: 96.6%.

Example 116(R)-3-((5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)-2-fluoropropan-1-ol

¹H NMR: 400 MHz, CD₃OD: δ 1.31-1.35 (m, 6H), 3.60-3.84 (m, 5H),4.68-4.70 (m, 1H), 6.17 (s, 1H), 7.52-7.59 (m, 2H), 7.97 (d, J=8.80 Hz,1H), 8.35 (s, 1H), 8.42 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS:Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H₂O: 20 mMNH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient 0-100% Bover 1.5 min (3.2 min run time); retention time: 1.482 min; LCMS(ES-API), m/z 442.2 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 5.274 min; Purity: 96.8%.

Example 117N2-(Benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-morpholino-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine

¹H NMR: 400 MHz, CD₃OD: δ 1.31-1.35 (m, 6H), 3.58-3.60 (m, 4H),3.78-3.86 (m, 5H), 6.17 (s, 1H), 7.54 (dd, J=2.00, 8.80 Hz, 1H), 7.98(d, J=8.80 Hz, 1H), 8.38 (s, 1H), 8.43 (d, J=2.00 Hz, 1H), 9.08 (s, 1H).LC/MS: Purospher@star RP-18, 4×55 mm, 3 m; Solvent A=10% ACN: 90% H₂O:20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient0-100% B over 1.5 min (3.2 min run time); retention time: 1.746 min;LCMS (ES-API), m/z 438.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 6.072 min; Purity: 96.8%.

Example 1181-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)piperidin-4-ol

¹H NMR: 400 MHz, CD₃OD: δ 1.31-1.34 (m, 6H), 1.61-1.70 (m, 2H),1.99-2.03 (m, 2H), 3.39-3.42 (2H, merged with water peak), 3.77-3.82 (m,1H), 3.88-3.94 (m, 3H), 6.16 (s, 1H), 7.52-7.58 (m, 2H), 7.96-7.98 (m,1H), 8.37 (s, 1H), 8.42 (d, J=2.00 Hz, 1H), 9.07 (s, 1H). LC/MS:Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min; retention time: 1.731 min; LCMS (ES-API), m/z 452.0 (M+H).HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O:0.05% TFA pH'² 2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 5.801 min; Purity: 97.5%.

Example 1191-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)piperidin-3-ol

¹H NMR: 400 MHz, CD₃OD: δ 1.33-1.37 (m, 6H), 1.64-1.66 (m, 2H),1.98-2.00 (m, 2H), 3.64-3.66 (m, 1H), 3.78-3.86 (m, 4H), 6.20 (s, 1H),7.55 (dd, J=2.00, 8.80 Hz, 1H), 7.91 (s, 1H), 8.16-8.18 (m, 3H), 9.28(s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.70 □μm; Solvent A=2%ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min; retention time: 1.757 min; LCMS(ES-API), m/z 452.0 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 6.620 min; Purity: 89.2%.

Example 120N2-(Benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-((tetrahydro-2H-pyran-4-yl)amino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine

¹H NMR: 400 MHz, CD₃OD: δ 1.34 (d, J=6.40 Hz, 6H), 1.60-1.70 (m, 2H),2.06-2.09 (m, 2H), 3.50-3.59 (m, 2H), 3.70-3.80 (m, 2H), 3.98-4.03 (m,2H), 6.16 (s, 1H), 7.53 (dd, J=2.00, 9.00 Hz, 1H), 7.97 (d, J=8.80 Hz,1H), 8.33 (s, 1H), 8.41 (d, J=2.00 Hz, 1H), 9.09 (s, 1H). LC/MS:Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min; retention time: 1.769 min; LCMS (ES-API), m/z 452.0 (M+H).HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O:0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retentiontime: 11.908 min; Purity: 94.05%.

Example 121(1-(((5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)methyl)cyclopropyl)methanol

LCMS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 1.5 min; retention time: 1.742 min; LCMS (ES-API), m/z450.0 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5%ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFApH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0μL/min; Retention time: 5.676 min; Purity: 93.2%.

Example 1222-((5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)ethanol

¹H NMR: 400 MHz, CD₃OD: δ 1.31-1.35 (m, 6H), 3.45-3.51 (m, 3H),3.75-3.81 (m, 3H), 6.16 (s, 1H), 7.53 (dd, J=2.40, 8.80 Hz, 1H), 7.97(d, J=8.80 Hz, 1H), 8.34 (s, 1H), 8.42 (d, J=2.00 Hz, 1H), 9.08 (s, 1H).LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 1.5 min; retention time: 1.657 min; LCMS (ES-API), m/z412.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5%ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFApH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0μL/min; Retention time: 5.389 min; Purity: 93.2%.

Example 1234-((5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)-2-methylbutan-1-ol

¹H NMR: 400 MHz, DMSO-d₆: δ 0.89 (d, J=6.80 Hz, 3H), 1.28-1.36 (m, 7H),1.59-1.74 (m, 2H), 3.25 (4H, merged with water peak), 3.69-3.74 (m, 1H),4.46 (t, J=5.20 Hz, 1H), 6.16 (s, 1H), 7.53 (d, J=7.20 Hz, 1H), 7.58(dd, J=2.40, 9.00 Hz, 1H), 7.73 (t, J=5.60 Hz, 1H), 7.95 (d, J=8.80 Hz,1H), 8.29 (s, 1H), 8.68 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.31 (s, 1H).Mol. wt.: 453.57. LC/MS: Retention time: 1.987 min. Purity: 99.5%.

Example 1243-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-ylamino)-1-phenylpropan-1-ol

¹H NMR: 400 MHz, DMSO-d₆: δ 1.28 (d, J=6.00 Hz, 6H), 1.90-1.92 (m, 2H),3.69-3.73 (m, 1H), 4.66-4.70 (m, 1H), 5.31-5.32 (m, 1H), 6.16 (s, 1H),7.22-7.26 (m, 1H), 7.32-7.38 (m, 4H), 7.52 (d, J=7.20 Hz, 1H), 7.59 (dd,J=2.40, 8.80 Hz, 1H), 7.76 (t, J=5.60 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H),8.28 (s, 1H), 8.68 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.32 (s, 1H). Mol.wt.: 501.61. LC/MS: Retention time: 2.288 min. Purity: 99.5%.

Example 1251-(2-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-ylamino)ethyl)cyclopentanol

¹H NMR: 400 MHz, DMSO-d₆: δ 1.28 (d, J=6.40 Hz, 6H), 1.46-1.63 (m, 7H),1.71-1.72 (m, 2H), 1.80-1.84 (m, 2H), 3.38 (2H, merged with water peak),3.69-3.74 (m, 1H), 4.20 (s, 1H), 6.16 (s, 1H), 7.53 (d, J=6.80 Hz, 1H),7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.66 (t, J=5.60 Hz, 1H), 7.95 (d, J=8.80Hz, 1H), 8.29 (s, 1H), 8.68 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.31 (s,1H). Mol. wt.: 479.61. LC/MS: Retention time: 2.245 min. Purity: 96.5%.

Example 1261-(2-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-ylamino)ethyl)cyclopentanol

¹H NMR: 400 MHz, DMSO-d₆: δ 1.10 (d, J=6.40 Hz, 3H), 1.24-1.29 (m, 6H),1.60-1.68 (m, 2H), 1.98-2.03 (m, 2H), 3.70-3.74 (m, 2H), 4.52 (d, J=4.80Hz, 1H), 6.16 (s, 1H), 7.52 (d, J=7.20 Hz, 1H), 7.58 (dd, J=2.00, 9.00Hz, 1H), 7.69 (t, J=5.60 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.29 (s, 1H),8.68 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.32 (s, 1H). Mol. wt.: 439.54.LC/MS: Retention time: 1.986 min. Purity: 99.8%.

Example 127(1-((5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-ylamino)methyl)cyclopentyl)methanol

¹H NMR: 400 MHz, DMSO-d₆: δ 1.24-1.29 (m, 6H), 1.41-1.43 (m, 4H),1.56-1.58 (m, 4H), 1.98-2.01 (m, 2H), 3.23 (4H, merged with water peak),3.69-3.74 (m, 1H), 4.71 (t, J=5.60 Hz, 1H), 5.33 (t, J=4.80 Hz, 1H),6.17 (s, 1H), 7.49 (d, J=Hz, 1H), 7.59 (dd, J=2.00, 8.80 Hz, 1H), 7.71(t, J=6.00 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H), 8.30 (s, 1H), 8.67 (d,J=2.00 Hz, 1H), 9.15 (s, 1H), 9.32 (s, 1H). Mol. wt.: 479.61. LC/MS:Retention time: 2.364 min. Purity: 99.6%.

Example 1285-(5-(Azetidin-3-ylamino)-1,3,4-oxadiazol-2-yl)-N2-(benzo[d]thiazol-6-yl)-N4-isopropylpyridine-2,4-diamine

¹H NMR: 400 MHz, DMSO-d₆: δ 1.18-1.21 (m, 3H), 1.24-1.28 (m, 6H),3.67-3.82 (m, 1H), 4.02-4.20 (m, 4H), 4.57-4.62 (m, 1H), 6.27 (s, 1H),7.49-7.56 (m, 1H), 8.12-8.14 (m, 1H), 8.17-8.18 (m, 1H), 8.25-8.32 (m,1H), 8.94-8.96 (m, 1H), 9.19 (bs, 2H), 9.37-9.40 (m, 1H), 10.40 (bs,1H). Mol. wt.: 422.52. LC/MS: Retention time: 1.504 min. Purity: 95%.

Example 1292-(4-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)piperazin-1-yl)ethanol

¹H NMR: 400 MHz, DMSO-d₆: δ 1.28 (d, J=6.40 Hz, 6H), 2.46 (2H, mergedwith DMSO-d₆ peak), 2.56 (4H, merged with DMSO-d₆ peak), 3.49-3.57 (m,6H), 3.71-3.72 (m, 1H), 4.45 (t, J=5.20 Hz, 1H), 6.17 (s, 1H), 7.42 (d,J=6.80 Hz, 1H), 7.58 (dd, J=2.40, 9.00 Hz, 1H), 7.95 (d, J=8.80 Hz, 1H),8.45 (s, 1H), 8.70 (d, J=2.00 Hz, 1H), 9.15 (s, 1H), 9.35 (s, 1H). Mol.wt.: 480.6. LC/MS: Retention time: 1.878 min. Purity: 98.3%.

Example 130N2-(Benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(4-(2-morpholinoethyl)piperazin-1-yl)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine

¹H NMR: 400 MHz, DMSO-d₆: δ 1.28 (d, J=6.40 Hz, 6H), 2.38-2.40 (m, 4H),2.45 (4H, merged with DMSO-d₆ peak), 2.55 (4H, merged with DMSO-d₆peak), 3.48-3.50 (m, 4H), 3.55-3.58 (m, 4H), 3.69-3.72 (m, 1H), 6.16 (s,1H), 7.42 (d, J=7.20 Hz, 1H), 7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.95 (d,J=8.80 Hz, 1H), 8.45 (s, 1H), 8.70 (d, J=2.40 Hz, 1H), 9.15 (s, 1H),9.35 (s, 1H). Mol. wt.: 549.7. LC/MS: Retention time: 2.015 min. Purity:95.2%.

Example 131

Synthesis ofN2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine:To a stirred solution of tert-butyl4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate(Example 111) (250 mg, 0.3 mmol) in DCM (10 mL), Ether.HCl (10 mL) wasadded at −10° C. Stirred the reaction mixture at 0° C. for 30 min.Reaction temperature was slowly brought to room temperature. Thereaction mass was concentrated under reduced pressure to dryness. Thematerial obtained was purified by prep. HPLC to afford the titlecompound,N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine¹H NMR: 400 MHz, CD₃OD: δ 1.37 (d, J=6.40 Hz, 6H), 1.90-2.00 (m, 2H),2.33-2.37 (m, 2H), 3.20-3.29 (m, 2H), 3.50-3.53 (m, 2H), 3.87-3.93 (m,2H), 6.28 (s, 1H), 7.63 (dd, J=1.20, 8.40 Hz, 1H), 8.21-8.27 (m, 3H),9.54 (bs, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 m; Solvent A=10%ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc;gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.277min; LCMS (ES-API), m/z 451.2 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min runtime); Flow rate: 1.0 μL/min; Retention time: 8.965 min; Purity: 98.1%.

Example 132N2-(Benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine

To a stirred solution ofN2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine(Example 131) (30 mg, 0.06 mmol) in DCM (4 mL): THF (4 mL), added DIPEA(0.09 mmol, 1.5 equiv.) and DMAP (0.006 mmol, 0.1 equiv.) and stirredfor 5 min. Added mesyl chloride (0.5 mmol, 0.8 equiv.) dropwise at 0° C.Stirred the reaction mixture at 0° C. for 1 h, reaction temperature wasbrought to room temperature and stirred overnight. The reaction mixturewas diluted with DCM. The DCM layer was washed with 10% NaHCO₃ solutionfollowed by water. The DCM layer was collected, dried over Na₂SO₄,filtered and concentrated. The material obtained was purified by prepHPLC to afford the title compound,N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-((1-(methylsulfonyl)piperidin-4-yl)amino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine.¹H NMR: 400 MHz, CD₃OD: δ 1.34 (d, J=6.40 Hz, 6H), 1.66-1.75 (m, 2H),2.10-2.14 (m, 2H), 3.027 (s, 3H), 3.30-3.36 (1H, merged with waterpeak), 3.56-3.60 (m, 1H), 3.78-3.82 (m, 1H), 4.00-4.05 (m, 2H), 6.17 (s,1H), 7.53-7.57 (m, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.38 (s, 1H), 8.43 (d,J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm;Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1%TFA; gradient 0-100% B over 2 min (3 min run time); retention time:1.501 min; LCMS (ES-API), m/z 529.2 (M+H). HPLC: Sunfire C18 (150×4.6mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; SolventB=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23min run time); Flow rate: 1.0 μL/min; Retention time: 5.771 min; Purity:99.7%.

Example 1331-(4-((5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidin-1-yl)ethanone

To a stirred solution ofN2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine(Example 131) (40 mg, 0.08 mmol) in DCM (5 mL): THF (5 mL), added DIPEA(0.08 mmol, 1.5 equiv.) and DMAP (0.008 mmol, 0.1 equiv.) and stirredfor 5 min. Added acetyl chloride (0.8 mmol, 0.8 equiv.) dropwise at 0°C. Stirred the reaction mixture at 0° C. for 1 h, the reactiontemperature was raised to room temperature and stirred overnight. Thereaction mixture was diluted with DCM. The DCM layer was washed with 10%NaHCO₃ solution followed by water. The DCM layer was collected, driedover Na₂SO₄, filtered and concentrated. The material obtained waspurified by prep HPLC to afford the title compound,1-(4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidin-1-yl)ethanone.¹H NMR: 400 MHz, CD₃OD: δ 1.34 (d, J=6.40 Hz, 6H), 1.57-1.66 (m, 2H),1.97 (s, 3H), 2.00-2.06 (m, 2H), 3.77-3.82 (m, 1H), 3.93-3.98 (m, 1H),4.03-4.06 (m, 2H), 6.17 (s, 1H), 7.53-7.56 (m, 1H), 7.98 (d, J=8.80 Hz,1H), 8.38 (s, 1H), 8.43 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: ZORBAXSB C18, 4.6×50 mm, 50 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA;Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3min run time); retention time: 1.514 min; LCMS (ES-API), m/z 493.2(M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 5.396 min; Purity: 99.4%.

Synthesis of2-chloro-5-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-N-isopropylpyridin-4-amine(46): To a stirred solution of6-chloro-4-(isopropylamino)nicotinohydrazide (10) (500 mg, 2 mmol) inDCM (10 mL), Et₃N (6 mmol, 3 equiv.) and 2-chloroacetyl chloride (3mmol, 1.5 equiv.) were added and stirred at room temperature for 4 h.Added tosyl chloride (3.2 mmol, 1.5 equiv.) was added at stirredovernight at room temperature. The reaction mixture was diluted withDCM. The DCM layer was washed with 10% NaHCO₃ solution followed bywater. The organic layer was collected, dried over Na₂SO₄, filtered andconcentrated. The crude material obtained was purified by columnchromatography through silica gel and EtOAc: Pet. ether as eluent toafford the desired compound,2-chloro-5-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-N-isopropylpyridin-4-amine.LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.95 min; LCMS (ES-API), m/z 287.6 (M+H).

Synthesis of2-chloro-N-isopropyl-5-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)pyridin-4-amine(47):2-chloro-5-(5-(chloromethyl)-1,3,4-oxadiazol-2-yl)-N-isopropylpyridin-4-amine(46) (60 mg, 0.2 mmol) was taken in a rbf, added morpholine (4 mL) tothe rbf followed by the addition of potassium iodide (0.2 mmol), stirredthe reaction mixture overnight at room temperature. The reaction mixturewas concentrated under reduced pressure to remove excess of morpholine.The crude material obtained was taken to next step as such, withoutpurification. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10%ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc;gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.608min; LCMS (ES-API), m/z 338.2 (M+H).

Example 1344-((4-(Isopropylamino)-5-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)amino)benzonitrile

To solution of2-chloro-N-isopropyl-5-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)pyridin-4-amine(47) (100 mg, 0.2 mmol) in dioxane (5 mL): H₂O (1 mL), 4-cyano aniline(0.3 mmol, 1.1 equiv.), xanthphos (0.1 mmol, 0.5 equiv.) and Na₂CO₃ (0.8mmol, 3 equiv.) were added and degassed for 10 min. To the reactionmixture Pd₂(dba)₃ (0.1 mmol, 0.5 equiv.) was added and degassed againfor 10 min. It was then heated at 110° C. for overnight. The reactionmass was cooled and filtered through small pad of celite. The filtrateobtained was concentrated to provide crude material. The crude materialwas purified by column chromatography through silica gel and MeOH: DCMas eluent. The material obtained was repurified on preparative TLC toafford4-((4-(isopropylamino)-5-(5-(morpholinomethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)amino)benzonitrile.¹H NMR: 400 MHz, CD₃OD: δ 1.37 (d, J=6.40 Hz, 6H), 2.67 (t, J=4.8 Hz,4H), 3.77 (t, J=4.4 Hz, 4H), 3.87 (q, J=6.4 Hz, 1H), 3.94 (s, 2H), 6.24(s, 1H), 7.61-7.64 (m, 2H), 7.72 (d, J=6.4 Hz, 1H), 7.77-7.80 (m, 2H),8.57 (s, 1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 μm; Solvent A=2%ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.595min; LCMS (ES-API), m/z 420.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 5.964 min; Purity: 95.1%.

Synthesis of 3-((tert-butyldimethylsilyl)oxy)propan-1-amine (48): To astirred solution of 3-aminopropan-1-ol (2 g, 20 mmol) in DCM (10 mL),imidazole (79 mmol, 3 equiv.) was added and stirred at room temperaturefor 10 min. Reaction mixture was cooled to 0° C., t-butyl dimethyl silylchloride (30 mmol, 1.2 equiv.) was added in portions and stirred thereaction mixture overnight at room temperature. Diluted the reactionmixture using DCM, the DCM layer was washed with water. The organiclayer was collected, dried over Na₂SO₄, filtered and concentrated. ELSDmethod LC/MS: Retention time: 1.5 min; (ES-API), m/z 189.7 (M+H).

Synthesis of5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one(49): 6-chloro-4-(isopropylamino)nicotinohydrazide (10) (800 mg, 3.5mmol) was taken in DMF (4 mL). Added CDI (3.8 mmol, 1.1 equiv.) andstirred at room temperature for overnight. The reaction mass wasconcentrated under reduced pressure to remove excess of DMF. The residuewas diluted using EtOAc, washed the EtOAc layer with water followed bybrine solution. Collected the EtOAc layer, dried over Na₂SO₄, filteredand concentrated. The crude material obtained was taken to next step assuch, without purification. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient0-100% B over 2 min; retention time: 0.76 min; LCMS (ES-API), m/z 255.6(M+H).

Synthesis ofN-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinecarboxamide(50):5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2(3H)-one(49) (1.2 g, 4 mmol) and 3-((tert-butyldimethylsilyl)oxy)propan-1-amine(48) (7 mmol, 1.5 equiv.) were dissolved in ethanol (5 mL). Refluxed thereaction mixture at 90° C., overnight. The reaction mass wasconcentrated under reduced pressure to remove excess of solvent. Thecrude material obtained was taken to next step as such, withoutpurification. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; SolventA=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2min; retention time: 1.02 min; LCMS (ES-API), m/z 444.9 (M+H).

Synthesis ofN-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-amine(51):N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinecarboxamide(50) (1 g, 2.2 mmol) in DCM (40 mL) was stirred at room temperature.Added triphenyl phosphine (6 mmol, 3 equiv.), Et₃N (18 mol, 8 equiv.)and CCl₄ (6 mmol, 3 equiv.). The reaction mixture was heated at 50° C.for 3 h. Reaction mixture was diluted using DCM. The DCM layer waswashed with water. The organic layer was collected, dried over Na₂SO₄,filtered and concentrated. The crude material was purified by columnchromatography through silica gel and EtOAc: Pet. Ether as eluent toprovide the desired compound,N-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-amine.LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 1.2 min; LCMS (ES-API), m/z 426.9 (M+H).

Synthesis of4-((5-(5-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-1,3,4-oxadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile(52a) andN2-(benzo[d]thiazol-6-yl)-5-(5-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-1,3,4-oxadiazol-2-yl)-N4-isopropylpyridine-2,4-diamine(52b): Followed the same procedure as mentioned in the synthesis ofExample 134 using their respective starting materials and appropriateamines.

LC/MS (Compound 52a): XBridge Phe 8, □4.6×30 mm, 3.5 μm; Solvent A=2%ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.922min; LCMS (ES-API), m/z 506.0 (M−H).

LC/MS (Compound 52b): Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10%ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc;gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.524min; LCMS (ES-API), m/z 540.2 (M+H).

Example 135

Synthesis of4-((5-(5-((3-hydroxypropyl)amino)-1,3,4-oxadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile:N2-(benzo[d]thiazol-6-yl)-5-(5-((3-((tert-butyldimethylsilyl)oxy)propyl)amino)-1,3,4-oxadiazol-2-yl)-N4-isopropylpyridine-2,4-diamine(52a) (150 mg, 0.2 mmol) in THF (10 mL) was cooled to 0° C. Added TBAF(1M in THF) (2 equiv.) to the reaction mixture. Reaction mixture waswarmed to room temperature and stirred for 1 h. Reaction mixture wasquenched by using 10% NaHCO₃ solution. The aqueous layer was extractedwith EtOAc (twice). The organic layers were collected together, driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedby column chromatography through silica gel and MeOH: DCM as eluent. Thematerial obtained was further purified by prep HPLC to provide thedesired compound,4-((5-(5-((3-hydroxypropyl)amino)-1,3,4-oxadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile.¹H NMR: 400 MHz, CD₃OD: δ 1.35 (d, J=6.40 Hz, 6H), 1.89-1.96 (m, 2H),3.46 (t, J=6.80 Hz, 2H), 3.71 (t, J=6.00 Hz, 2H), 3.79-3.83 (m, 1H),6.21 (s, 1H), 7.58-7.65 (m, 3H), 7.73-7.76 (m, 2H), 8.37 (s, 1H). LC/MS:XBridge Phe 8, □4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H₂O: 10 mMNH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min (3.2 min run time); retention time: 1.486 min; LCMS(ES-API), m/z 394.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 5.812 min; Purity: 99.4%.

Example 136

Synthesis of3-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)propan-1-ol:Followed the same procedure as mentioned in the synthesis of Example135. ¹H NMR: 400 MHz, CD₃OD: δ 1.34 (d, J=6.40 Hz, 6H), 1.88-1.94 (m,2H), 3.46 (t, J=7.20 Hz, 2H), 3.71 (t, J=6.00 Hz, 2H), 3.78-3.82 (m,1H), 6.16 (s, 1H), 7.54 (dd, J=2.00, 8.80 Hz, 1H), 7.60 (d, J=6.80 Hz,1H), 7.97 (d, J=8.80 Hz, 1H), 8.34 (s, 1H), 8.42 (d, J=2.00 Hz, 1H),9.08 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 m; Solvent A=10%ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc;gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.443min; LCMS (ES-API), m/z 424.2 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 5.157 min; Purity: 99.1%.

Synthesis of tert-butyl(2-((tert-butyldimethylsilyl)oxy)-1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate(55)

Step 1: To a stirred solution of2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid (500 mg, 2.4mmol) and 6-chloro-4-(isopropylamino)nicotinohydrazide (10) (2.6 mmol,1.1 equiv.) in DMF (10 mL), DIPEA (12 mmol, 5 equiv.) and HATU (2.6mmol, 1.1 equiv.) were added and stirred overnight at room temperature.The reaction mass was concentrated under reduced pressure to removeexcess of solvent present. Diluted the residue with EtOAc and washedwater followed by brine solution. The organic layer was collected, driedover Na₂SO₄, filtered and concentrated to get tert-butyl(1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-3-hydroxy-1-oxopropan-2-yl)carbamate(53).

Step 2: tert-Butyl(1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-3-hydroxy-1-oxopropan-2-yl)carbamate(53) (1 g, 2 mmol) in DCM (10 mL), imidazole (7 mmol, 3 equiv.) wasadded and stirred at room temperature for 10 min. Reaction mixture wascooled to 0° C., t-butyl dimethyl silyl chloride (3.6 mmol, 1.5 equiv.)was added in portions and stirred the reaction mixture overnight at roomtemperature. Diluted the reaction mixture using DCM, the DCM layer waswashed with water. The organic layer was collected, dried over Na₂SO₄,filtered and concentrated to get tert-butyl(3-((tert-butyldimethylsilyl)oxy)-1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate(54). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90%H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient0-100% B over 1.5 min (3.2 min run time); retention time: 2.319 min;LCMS (ES-API), m/z 530.2 (M+H).

Step 3: tert-Butyl(3-((tert-butyldimethylsilyl)oxy)-1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate(54) (100 mg, 0.18 mmol) in DCM (5 mL) was stirred at room temperature.Added triphenyl phosphine (0.56 mmol, 3 equiv.), Et₃N (1.5 mol, 8equiv.) and CCl₄ (0.56 mmol, 3 equiv.). The reaction mixture was heatedat 50° C. for 3 h. Reaction mixture was diluted using DCM. The DCM layerwas washed with water. The organic layer was collected, dried overNa₂SO₄, filtered and concentrated. The crude material was purified bycolumn chromatography through silica gel and EtOAc: Pet. Ether as eluentto provide the desired compound, tert-butyl(2-((tert-butyldimethylsilyl)oxy)-1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate(55). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90%H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient0-100% B over 1.5 min (3.2 min run time); retention time: 2.567 min;LCMS (ES-API), m/z 512.3 (M+H).

Synthesis of tert-butyl(1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate(56): Followed the same procedure as mentioned in the synthesis ofExample 134, using respective starting materials. LC/MS: XBridge Phe 8,□4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; SolventB=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2min run time); retention time: 1.975 min; LCMS (ES-API), m/z 626.0(M+H).

Example 137

Synthesis of tert-butyl(1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-hydroxyethyl)carbamate:Followed the same procedure as mentioned in the synthesis of Example135. ¹H NMR: 400 MHz, CD₃OD: δ 1.31-1.49 (m, 15H), 3.05 (bs, 1H),3.79-3.86 (m, 1H), 3.98 (d, J=5.60 Hz, 2H), 5.06 (bs, 1H), 6.18 (s, 1H),7.55 (dd, J=2.00, 8.80 Hz, 1H), 7.65 (d, J=7.20 Hz, 1H), 7.98 (d, J=8.80Hz, 1H), 8.43 (d, J=2.00 Hz, 1H), 8.52 (s, 1H), 9.09 (s, 1H). LC/MS:ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA;Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3min run time); retention time: 1.654 min; LCMS (ES-API), m/z 512.2(M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 6.518 min; Purity: 92.3%.

Example 138

Synthesis of2-amino-2-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl):tert-butyl(1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate(56) (60 mg, 0.096 mmol) was dissolved in DCM (5 mL), cooled to 0° C.Added ether.HCl (5 mL) to the reaction mixture, stirred at 0° C. for 10min. Gradually the reaction temperature was raised to room temperatureand stirred for 30 min. The reaction mass was concentrated under reducedpressure. The crude material obtained was purified by prep. HPLC toafford the desired compound,2-amino-2-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethanol.¹H NMR: 400 MHz, CD₃OD: δ 1.39 (d, J=6.40 Hz, 6H), 3.88-3.94 (m, 1H),4.15 (d, J=8.00 Hz, 2H), 4.97 (t, J=4.80 Hz, 1H), 6.27 (s, 1H), 7.58(dd, J=2.40, 8.80 Hz, 1H), 8.17 (d, J=2.40 Hz, 1H), 8.23 (d, J=8.80 Hz,1H), 8.39 (s, 1H), 9.35 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3μm; Solvent A=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10%H₂O: 20 mM NH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time);retention time: 1.359 min; LCMS (ES-API), m/z 412.2 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time:8.639 min; Purity: 98.4%.

Synthesis of5-(5-(1-amino-2-((tert-butyldimethylsilyl)oxy)ethyl)-1,3,4-oxadiazol-2-yl)-N2-(benzo[d]thiazol-6-yl)-N4-isopropylpyridine-2,4-diamine(57): tert-butyl(1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate(56) (200 mg, 0.3 mmol) was dissolved in DCM (10 mL), cooled to −10° C.Added 2,6-lutidine (1.9 mmol, 6 equiv.) and stirred for 15 min. AddedTBDMS-Triflate (1.6 mmol, 5 equiv.) in portions, dropwise to thereaction mixture and stirred at −10° C. for 30 min. Gradually, thereaction temperature was raised to room temperature and stirred for 30min. Diluted the reaction mixture using DCM and quenched by addition of5% citric acid solution. Extracted the reaction mixture in DCM. Theorganic layer was collected, dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by column chromatographythrough silica gel and MeOH: DCM as eluent to provide the desiredcompound,5-(5-(1-amino-2-((tert-butyldimethylsilyl)oxy)ethyl)-1,3,4-oxadiazol-2-yl)-N2-(benzo[d]thiazol-6-yl)-N4-isopropylpyridine-2,4-diamine.LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.79 min; LCMS (ES-API), m/z 526.9 (M+H).

Synthesis ofN-(1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)methanesulfonamide(58): Followed the same procedure as mentioned in the synthesis ofExample 132. LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 μm; Solvent A=2% ACN:98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.846min; LCMS (ES-API), m/z 604.2 (M+H).

Example 139

Synthesis ofN-(1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-hydroxyethyl)methanesulfonamide:Followed the same procedure as mentioned in the synthesis of Example135. ¹H NMR: 400 MHz, CD₃OD: δ 1.36 (d, J=6.40 Hz, 6H), 3.06 (s, 3H),3.79-3.86 (m, 1H), 4.03 (d, J=6.00 Hz, 1H), 4.97 (t, J=6.00 Hz, 2H),6.19 (s, 1H), 7.56 (dd, J=2.40, 8.80 Hz, 1H), 7.99 (d, J=8.80 Hz, 1H),8.45 (d, J=2.00 Hz, 1H), 8.55 (s, 1H), 9.09 (s, 1H). LC/MS:Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H₂O: 20 mMNH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient 0-100% Bover 1.5 min (3.2 min run time); retention time: 1.490 min; LCMS(ES-API), m/z 490.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 5.484 min; Purity: 99.9%.

Example 140 Synthesis ofN2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine

Step 1: 6-Chloro-4-(isopropylamino)nicotinohydrazide (10) (500 mg, 2.1mmol) and benzoic acid (2.1 mmol, 1 equiv.) were dissolved in DMF (10mL). EDC.HCl (1.5 equiv.), DIPEA (3 equiv.) and HOBT (1.5 equiv.) wereadded to the reaction mixture and stirred at room temperature for 5 h.The reaction mass was concentrated under reduced pressure to removeexcess of solvent present. Diluted the residue with EtOAc and washedwater followed by brine solution. The organic layer was collected, driedover Na₂SO₄, filtered and concentrated to getN′-benzoyl-6-chloro-4-(isopropylamino)nicotinohydrazide.

Step 2: The crude material ofN′-benzoyl-6-chloro-4-(isopropylamino)nicotinohydrazide was dissolved inDCM (15 mL). Tosyl chloride (1.5 equiv.) and triethyl amine (3 equiv.)were added to the reaction mixture and stirred overnight at roomtemperature. Reaction mixture was diluted using DCM. The DCM layer waswashed with water. The organic layer was collected, dried over Na₂SO₄,filtered and concentrated. The crude material was purified by columnchromatography through silica gel and MeOH:DCM as eluent to provide thedesired compound,2-chloro-N-isopropyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-4-amine

Step 3: To solution of2-chloro-N-isopropyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-4-amine(200 mg, 0.6 mmol) in dioxane (10 mL): H₂O(2 mL), 6-amino benzothiazole(0.63 mmol, 1 equiv.), xanthphos (0.2 mmol, 0.4 equiv.) and Na₂CO₃ (2.5mmol, 4 equiv.) were added and degassed for 10 min. To the reactionmixture Pd₂(dba)₃ (0.2 mmol, 0.4 equiv.) was added and degassed againfor 10 min. It was then heated at 110° C. for overnight. The reactionmass was cooled and filtered through small pad of celite. The filtrateobtained was concentrated to provide crude material. The crude materialwas purified by column chromatography through silica gel and MeOH: DCMas eluent. The material obtained was further purified by prep. HPLC toaffordN2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine.

¹H NMR: 400 MHz, DMSO-d₆: δ 1.33 (d, J=6.40 Hz, 6H), 3.74-3.82 (m, 1H),6.23 (s, 1H), 7.56-7.57 (m, 1H), 7.61-7.67 (m, 4H), 7.98 (d, J=8.80 Hz,1H), 8.15-8.17 (m, 2H), 8.71 (d, J=2.00 Hz, 1H), 8.78 (s, 1H), 9.18 (s,1H), 9.50 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 m; SolventA=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mMNH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 2.332 min; LCMS (ES-API), m/z 429.2 (M+H). HPLC: XBridge Phenyl(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 9.891 min;Purity: 94.5%.

Synthesis of Examples 141-148: Followed the same procedure as mentionedfor the synthesis of Example 140, using appropriate starting materials.

TABLE 8

Example No. R R₁ 140

141

142

143

144

145

146

147

148

Example 1414-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)benzenesulfonamide

¹H NMR: 400 MHz, CD₃OD: δ 1.39 (d, J=6.40 Hz, 6H), 3.84-3.87 (m, 1H),6.22 (s, 1H), 7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.99-8.01 (m, 1H),8.13-8.15 (m, 2H), 8.33-8.35 (m, 2H), 8.49 (d, J=2.00 Hz, 1H), 8.72 (s,1H), 9.10 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.881 min;LCMS (ES-API), m/z 508.0 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 7.774 min; Purity: 99.5%.

Example 142N2-(Benzo[d]thiazol-6-yl)-5-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-N4-isopropylpyridine-2,4-diamine

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30-1.31 (m, 6H), 1.36-1.48 (m, 2H),1.57-1.70 (m, 3H), 1.76-1.80 (m, 2H), 2.06-2.09 (m, 2H), 3.01-3.07 (m,1H), 3.72-3.77 (m, 1H), 6.20 (s, 1H), 7.54 (d, J=7.20 Hz, 1H), 7.60 (dd,J=2.80, 9.20 Hz, 1H), 7.96-7.99 (m, 1H), 8.52 (s, 1H), 8.69 (d, J=2.00Hz, 1H), 9.18 (s, 1H), 9.43 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1mm, 2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98%ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min; retentiontime: 2.273 min; LCMS (ES-API), m/z 435.2 (M+H). HPLC: Sunfire C18(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 8.135 min;Purity: 98.3%.

Example 1435-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-N-(tert-butyl)-2-fluorobenzenesulfonamide

¹H NMR: 400 MHz, CD₃OD: δ 1.19 (s, 9H), 1.33 (d, J=6.40 Hz, 6H),3.75-3.80 (m, 1H), 6.22 (s, 1H), 7.50 (d, J=7.20 Hz, 1H), 7.61 (dd,J=2.00, 9.20 Hz, 1H), 7.73 (t, J=9.20 Hz, 1H), 7.97-7.99 (m, 1H), 8.08(s, 1H), 8.42-8.45 (m, 1H), 8.50-8.52 (m, 1H), 8.72 (d, J=2.00 Hz, 1H),8.79 (d, J=Hz, 1H), 9.18 (s, 1H), 9.50 (s, 1H). LC/MS: Ascentis ExpressC18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH;Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5min; retention time: 2.107 min; LCMS (ES-API), m/z 582.0 (M+H). HPLC:Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05%TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100%B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:8.135 min; Purity: 95%.

Example 1445-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-fluorophenol

¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.40 Hz, 6H), 3.76-3.81 (m, 1H),6.23 (s, 1H), 7.40-7.44 (m, 1H), 7.59-7.61 (m, 2H), 7.71-7.73 (m, 2H),8.02 (d, J=8.40 Hz, 1H), 8.62 (bs, 1H), 8.69 (s, 1H), 9.22 (s, 1H), 9.59(bs, 1H), 10.52 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.973 min;LCMS (ES-API), m/z 461.0 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μl/min; Retention time: 7.283 min; Purity: 95.5%.

Example 1452-(5-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-fluorophenoxy)ethanol

¹H NMR: 400 MHz, DMSO-d₆: δ 1.33 (d, J=6.40 Hz, 6H), 3.80-3.83 (m, 3H),4.25-4.27 (m, 2H), 4.97-5.00 (m, 1H), 6.22 (s, 1H), 7.47-7.55 (m, 2H),7.61-7.63 (m, 1H), 7.72-7.78 (m, 1H), 7.88-7.90 (m, 1H), 7.90-7.99 (m,1H), 8.73 (d, J=2.40 Hz, 1H), 8.87 (s, 1H), 9.18 (s, 1H), 9.49 (s, 1H).LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 1.5 min; retention time: 1.954 min; LCMS (ES-API), m/z507.0 (M+H). HPLC: XBridge (150×4.6 mm), 3.5 micron; Solvent A=5% ACN:95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0l/min;Retention time: 8.259 min; Purity: 97.6%.

Example 1465-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-N-cyclopropyl-2-fluorobenzenesulfonamide

¹H NMR: 400 MHz, DMSO-d₆: δ 0.46-0.47 (m, 2H), 0.54-0.56 (m, 2H),1.15-1.25 (m, 1H), 1.34 (d, J=6.40 Hz, 6H), 3.76-3.81 (m, 1H), 6.23 (s,1H), 7.51 (d, J=6.80 Hz, 1H), 7.62 (dd, J=2.00, 9.00 Hz, 1H), 7.78 (t,J=8.80 Hz, 1H), 7.99 (d, J=8.80 Hz, 1H), 8.48-8.51 (m, 3H), 8.73 (d,J=1.60 Hz, 1H), 8.80 (s, 1H), 9.19 (s, 1H), 9.51 (s, 1H). LC/MS: ZORBAXSB C18, 4.6×50 mm, 50 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA;Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3min run time); retention time: 1.726 min; LCMS (ES-API), m/z 566.0(M+H). HPLC: XBridge (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μl/min;Retention time: 8.941 min; Purity: 96.9%.

Example 1475-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzenesulfonamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.34 (d, J=6.40 Hz, 6H), 3.76-3.81 (m, 1H),6.23 (s, 1H), 7.52 (d, J=7.20 Hz, 1H), 7.61-7.64 (m, 1H), 7.74 (t,J=9.20 Hz, 1H), 7.96-8.00 (m, 3H), 8.32 (s, 1H), 8.42-8.45 (m, 1H),8.50-8.52 (m, 1H), 8.71 (d, J=2.00 Hz, 1H), 8.79 (s, 1H), 9.19 (s, 1H),9.52 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10%MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient0-100% B over 2 min (3 min run time); retention time: 1.576 min; LCMS(ES-API), m/z 526.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μl/min; Retention time: 6.771 min; Purity: 94.1%.

Example 1483-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)benzamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.33-1.37 (m, 6H), 3.79-3.81 (m, 1H), 6.24(s, 1H), 7.60-7.63 (m, 3H), 7.74 (t, J=7.60 Hz, 1H), 8.01 (d, J=8.80 Hz,1H), 8.15 (d, J=8.00 Hz, 1H), 8.25 (s, 1H), 8.30 (d, J=7.60 Hz, 1H),8.63-8.65 (m, 2H), 8.80 (s, 1H), 9.22 (s, 1H), 9.60 (s, 1H). LC/MS:Ascentis Express C18, 5×2.1 mm, 2.7□μm; Solvent A=2% ACN: 98% H₂O: 10 mMNH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min; retention time: 1.839 min; LCMS (ES-API), m/z 470.0 (M−H).HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O:0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient0-100% B over 15 min (23 min run time); Flow rate: 1.0 μl/min; Retentiontime: 6.51 min; Purity: 91.1%.

TABLE 9

Com- pound No. R R₁ R₂ 149

CH₃ 150

H

Step 1: To solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2)in dioxane (5 mL): H₂O(1 mL), 4-fluoro aniline (1 equiv.), xanthphos(0.4 equiv.) and Na₂CO₃ (4 equiv.) were added and degassed for 10 min.To the reaction mixture Pd₂(dba)₃ (0.4 equiv.) was added and degassedagain for 10 min. It was then heated at 115° C., overnight. The reactionmass was cooled and filtered through small pad of celite. The filtrateobtained was concentrated to provide crude material. The crude materialwas purified by column chromatography through silica gel and MeOH: CHCl₃as eluent to afford C-4 and C-6 substituted compound 61.

Step 2: To a stirred solution of 61 in ethanol (10 mL), hydrazinehydrate (3 mL) was added and refluxed at 80° C. for 3 h. The reactionmixture was cooled and concentrated to obtain crude compound. Theresidue obtained was washed with diethyl ether and hexane to gethydrazide derivative compound,6-((4-fluorophenyl)amino)-4-(isopropylamino)nicotinohydrazide (62).

Step 3: A solution of6-((4-fluorophenyl)amino)-4-(isopropylamino)nicotinohydrazide (91) (100mg) and PTSA(10 mg) in trimethyl orthoacetate (5 mL) was heated at 100°C., overnight. The reaction mixture was concentrated, diluted withEtOAc. The organic layer was washed with sat. NaHCO₃ solution, water andbrine solution. The organic layer was collected, dried over Na₂SO₄,filtered and concentrated. The crude material obtained was purified byprep. HPLC to affordN2-(4-fluorophenyl)-N4-isopropyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine(Example 149).

¹H NMR: 400 MHz, DMSO-d₆: δ 1.29 (d, J=6.00 Hz, 6H), 2.57 (3H, mergedwith DMSO-d₆ peak), 3.69-3.82 (m, 1H), 6.08 (s, 1H), 6.96-7.21 (m, 2H),7.60-7.63 (m, 3H), 8.39 (s, 1H), 9.20 (bs, 1H). LC/MS: XBridge Phe 8,□4.6×30 mm, 3.5 m; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; SolventB=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2min run time); retention time: 1.673 min; LCMS (ES-API), m/z 328.2(M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 6.545 min; Purity: 91.05%.

Example 150

Synthesis ofN2-(4-fluorophenyl)-N4-isopropyl-5-(1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine:Followed the same procedure as mentioned in the synthesis of Example149. Trimethyl orthoacetate was replaced by trimethyl orthoformate toget the desired compound. ¹H NMR: 400 MHz, DMSO-d₆: δ 1.30 (d, J=6.40Hz, 6H), 3.70-3.75 (m, 1H), 6.09 (s, 1H), 7.10-7.14 (m, 2H), 7.51-7.53(m, 1H), 7.63-7.66 (m, 2H), 8.47 (s, 1H), 9.16 (s, 1H), 9.24 (s, 1H).LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 m; Solvent A=2% ACN: 98% H₂O: 10mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min (3.2 min run time); retention time: 1.663 min; LCMS(ES-API), m/z 314.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.44 min; Purity: 97.9%.

Synthesis of C-6 substituted methyl5-(4-(isopropylamino)-pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate (65):Compounds of the general formula 64 were dissolved in DCM, addedtriethyl amine (3 equiv.) and cooled to 0° C. Added methyl oxalylchloride (1.2 equiv.) to the reaction mixture dropwise, stirred thereaction mixture at room temperature for 6 h. Added tosyl chloride (2equiv.) to the reaction mixture and stirred overnight at roomtemperature. The reaction mixture was quenched with sat. NaHCO₃ solutionand extracted in DCM. The organic layer was collected, dried overNa₂SO₄, filtered and concentrated. The crude material obtained waspurified by column chromatography, silica gel, MeOH: DCM as eluent toafford C-6 substituted methyl5-(4-(isopropylamino)-pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate.

Example 151

Synthesis of5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide:A solution of methyl5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate(derivative of 95) in MeOH (10 mL) was cooled to −10° C. and NH₃ (g) waspurged through the reaction mixture for 5 min. Heated the reaction for 4h in closed condition at 80° C. Cooled to 0° C. and transferred to rbfand concentrated. The crude material obtained was purified by prep. HPLCto afford the desired compound,5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide.¹H NMR: 400 MHz, CD₃OD: δ 1.36-1.38 (m, 6H), 3.82-3.86 (m, 1H), 6.19 (s,1H), 7.57 (dd, J=2.00, 9.00 Hz, 1H), 7.68 (d, J=7.20 Hz, 1H), 7.99 (d,J=8.80 Hz, 1H), 8.48 (d, J=2.00 Hz, 1H), 8.66 (s, 1H), 9.10 (s, 1H).LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H₂O: 10mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min (3.2 min run time); retention time: 1.465 min; LCMS(ES-API), m/z 396.2 (M+H). HPLC: XBridge (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.45 min; Purity: 95.2%.

Synthesis of Examples 152 and 153: Prepared according to the procedureoutlined for the synthesis Example 151, using appropriate startingmaterials.

TABLE 10

Example No. R₁ 151

152

153

Example 152(S)-5-(6-(Benzo[d]thiazol-6-ylamino)-4-((1-hydroxy-3-phenylpropan-2-yl)amino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide

¹H NMR: 400 MHz, CD₃OD: δ 2.90-2.95 (m, 1H), 3.02-3.07 (m, 1H),3.66-3.74 (m, 2H), 3.85-3.87 (m, 1H), 6.19 (s, 1H), 7.14-7.26 (m, 5H),7.53 (dd, J=2.40, 8.80 Hz, 1H), 7.98-8.02 (m, 1H), 8.36 (d, J=2.40 Hz,1H), 8.62 (s, 1H), 9.12 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm,2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2%H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min; retention time:1.682 min; LCMS (ES-API), m/z 488.4 (M+H). HPLC: XBridge Phenyl (150×4.6mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; SolventB=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23min run time); Flow rate: 1.0 μL/min; Retention time: 6.579 min; Purity:88.1%.

Example 1535-(6-((3,3-Difluoro-1-methyl-2-oxoindolin-5-yl)amino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.30 (d, J=6.40 Hz, 6H), 3.18 (s, 3H),3.70-3.77 (m, 1H), 6.09 (s, 1H), 7.19 (d, J=8.40 Hz, 1H), 7.52 (bs, 1H),7.68 (d, J=8.80 Hz, 1H), 8.14 (s, 1H), 8.26 (s, 1H), 8.58-8.61 (m, 2H),9.47 (bs, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; SolventA=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mMNH₄COOH; gradient 0-100% B over 1.5 min; retention time: 1.75 min; LCMS(ES-API), m/z 444.2 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 7.321 min; Purity: 98.4%.

TABLE 11

Example No. R₁ R₂ 154

155

156

Example 154

Synthesis of(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methanol:A solution of methyl5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate(200 mg) in THF (10 mL): MeOH (10 mL) was cooled to 0° C. Added LiBH₄ (3equiv.) in portions to the reaction mixture, stirred for 30 min at 0° C.Gradually the reaction temperature was raised to room temperature andstirred for 30 min. The reaction was quenched using ice pieces. Thereaction mass was concentrated under reduced pressure. The residueobtained was diluted with EtOAc. The organic layer was washed withwater. The organic layer was collected, dried over Na₂SO₄, filtered andconcentrated. The crude material obtained was purified by prep HPLC toafford the desired compound,(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methanol.¹H NMR: 400 MHz, DMSO-d₆: δ 657.15 (d, J=524681.20 Hz, 6H), 3.71-3.79(m, 1H), 4.71 (d, J=6.40 Hz, 2H), 5.93 (t, J=6.40 Hz, 1H), 6.21 (s, 1H),7.36-7.38 (m, 1H), 7.52 (d, J=7.20 Hz, 1H), 7.61 (dd, J=2.00, 8.80 Hz,1H), 7.97 (d, J=8.80 Hz, 1H), 8.49 (s, 1H), 8.65 (d, J=2.00 Hz, 1H),9.17 (s, 1H), 9.44 (s, 1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.454 min; LCMS (ES-API), m/z 383.2 (M+H). HPLC: Sunfire C18(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.528 min;Purity: 85.66%.

Example 155

Synthesis of2-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethanol:Followed the same procedure as mentioned in the synthesis of Example154, using appropriate starting materials. ¹H NMR: 400 MHz, CD₃OD: δ1.36 (d, J=6.40 Hz, 6H), 3.17 (t, J=6.40 Hz, 2H), 3.79-3.85 (m, 1H),4.03 (t, J=6.40 Hz, 2H), 6.18 (s, 1H), 7.56 (dd, J=2.40, 8.80 Hz, 1H),7.99 (d, J=8.80 Hz, 1H), 8.45 (d, J=2.00 Hz, 1H), 8.52 (s, 1H), 9.09 (s,1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.70 □μm; Solvent A=2% ACN:98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min; retention time: 1.641 min; LCMS(ES-API), m/z 396.9 (M−H). HPLC: XBridge (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.196 min; Purity: 97%.

Example 156

Synthesis of2-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)propan-2-ol:To a solution methyl5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate(150 mg) in dry Tetrahydrofuran (10 mL) was added methyl magnesiumbromide (3 equiv.) (3.0 M in diethyl ether) at −78° C. Reaction mixturewas allowed to warm up to 25° C. over 2 h. The reaction mixture wascooled to 0° C. and quenched by the addition of saturated aqueous NH₄Clsolution dropwise. Extracted with ethyl acetate, dried over Na₂SO₄,filtered and concentrated to get the crude product, which was purifiedby flash column using ethyl acetate/hexanes as eluent to fumish2-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)propan-2-ol.¹H NMR: 400 MHz, DMSO-d₆: δ 1.30 (d, J=6.40 Hz, 6H), 1.61 (s, 6H),3.71-3.79 (m, 1H), 5.89 (s, 1H), 6.20 (s, 1H), 7.51 (d, J=6.80 Hz, 1H),7.60 (dd, J=2.00, 8.80 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.54 (s, 1H),8.68 (d, J=2.40 Hz, 1H), 9.17 (s, 1H), 9.45 (s, 1H). LC/MS: AscentisExpress C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98% H₂O: 10 mMNH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min; retention time: 1.788 min; LCMS (ES-API), m/z 409.2 (M−H).HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O:0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retentiontime: 11.704 min; Purity: 98.6%.

Synthesis of methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate(66): Followed the same procedure as mentioned in the synthesis ofcompound no 65. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; SolventA=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mMNH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.821 min; LCMS (ES-API), m/z 297.2 (M+H).

Synthesis of(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(morpholino)methanone(67): A solution of methyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate(66) (150 mg, 0.51 mmol) in morpholine (1 mL) and MeOH (1 mL) was heatedat 80° C. for 2 h. The reaction mass was concentrated under reducedpressure. The crude material obtained was triturated with diethyl etherand filtered to get the desired compound,(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(morpholino)methanone.LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.88 min; LCMS (ES-API), m/z 352.7 (M+H).

TABLE 12

Example No. R R₁ 157

158

159

160

161

162

163

164

165

166

167

Example 157

Synthesis of(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(morpholino)methanone:To solution of(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(morpholino)methanonein dioxane (5 mL): H₂O(1 mL), 6-amino benzothiazole (1.2 equiv.),xanthphos (0.5 equiv.) and Na₂CO₃ (3 equiv.) were added and degassed for10 min. To the reaction mixture Pd₂(dba)₃ (0.5 equiv.) was added anddegassed again for 10 min. It was then heated at 115° C., overnight. Thereaction mass was cooled and filtered through small pad of celite. Thefiltrate obtained was concentrated to provide crude material. The crudematerial was purified by column chromatography through silica gel(230-400 mesh) and MeOH: CHCl₃ as eluent. It was further purified byprep HPLC to afford the title compound. ¹H NMR: 400 MHz, CD₃OD: δ1.31-1.38 (m, 6H), 3.81-3.86 (m, 7H), 4.19-4.22 (m, 2H), 6.19 (s, 1H),7.57 (dd, J=2.00, 8.60 Hz, 1H), 7.66-7.68 (m, 1H), 7.99 (d, J=8.80 Hz,1H), 8.48 (d, J=2.00 Hz, 1H), 8.63 (s, 1H), 9.10 (s, 1H). LC/MS: XBridgePhe 8, □4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH;Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min(3.2 min run time); retention time: 1.604 min; LCMS (ES-API), m/z 463.8(M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95%H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 6.224 min; Purity: 98.3%.

Synthesis of Examples 158-167: Followed the same method as mentioned forExample 157, using appropriate amines.

Example 158(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(3-hydroxypiperidin-1-yl)methanone

¹H NMR: 400 MHz, CD₃OD: δ 1.37 (d, J=6.40 Hz, 6H), 1.63-1.73 (m, 2H),1.97-2.06 (m, 2H), 3.74-3.87 (m, 4H), 4.15-4.16 (m, 1H), 6.19 (s, 1H),7.56 (dd, J=2.00, 7.20 Hz, 1H), 7.67 (d, J=7.20 Hz, 1H), 7.98 (d, J=8.80Hz, 1H), 8.48 (s, 1H), 8.62 (s, 1H), 9.09 (s, 1H). LC/MS: ZORBAX SB C18,4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90%MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time);retention time: 1.48 min; LCMS (ES-API), m/z 480.2 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:5.95 min; Purity: 98.8%.

Example 1594-((4-(Isopropylamino)-5-(5-(piperazine-1-carbonyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)amino)benzonitrile

¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.40 Hz, 6H), 3.23-3.32 (m, 4H),3.76-3.81 (m, 1H), 3.89 (m, 2H), 4.22 (m, 2H), 6.29 (s, 1H), 7.55-7.57(m, 1H), 7.70-7.72 (m, 2H), 7.88-7.90 (m, 2H), 8.55 (s, 1H), 8.81 (bs,1H), 9.81 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 m; SolventA=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mMNH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.552 min; LCMS (ES-API), m/z 431.2 (M−H). HPLC: Sunfire C18(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.062 min;Purity: 96.8%.

Example 1604-((5-(5-(4-Hydroxypiperidine-1-carbonyl)-1,3,4-oxadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile

¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.40 Hz, 6H), 1.43-1.51 (m, 2H),1.84-1.86 (m, 2H), 3.37-3.43 (m, 1H), 3.58-3.64 (m, 1H), 3.76-3.85 (m,2H), 3.98-4.04 (m, 1H), 4.12-4.18 (m, 1H), 4.86 (d, J=4.00 Hz, 1H), 6.27(s, 1H), 7.57 (d, J=6.80 Hz, 1H), 7.70-7.72 (m, 2H), 7.87-7.89 (m, 2H),8.53 (s, 1H), 9.76 (s, 1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 m;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.552 min; LCMS (ES-API), m/z 448.0 (M+H). HPLC: XBridge (150×4.6mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; SolventB=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23min run time); Flow rate: 1.0 μL/min; Retention time: 7.235 min; Purity:99.6%.

Example 161(4-Aminopiperidin-1-yl)(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methanone

¹H NMR: 400 MHz, CD₃OD: δ 1.37 (d, J=6.00 Hz, 6H), 1.62-1.76 (m, 2H),2.14-2.20 (m, 2H), 3.04-3.10 (m, 1H), 3.33-3.51 (4H, merged with waterpeak), 3.83-3.86 (m, 1H), 6.20 (s, 1H), 7.57 (dd, J=2.00, 8.80 Hz, 1H),8.00 (d, J=8.80 Hz, 1H), 8.47 (d, J=2.00 Hz, 1H), 8.63 (s, 1H), 9.11 (s,1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 m; Solvent A=2% ACN: 98% H₂O:10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100%B over 1.5 min (3.2 min run time); retention time: 1.434 min; LCMS(ES-API), m/z 479.0 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 5.613 min; Purity: 99.4%.

Example 162(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(4-hydroxypiperidin-1-yl)methanone

¹H NMR: 400 MHz, CD₃OD: δ 1.36-1.38 (m, 6H), 1.62-1.68 (m, 2H),2.00-2.03 (m, 2H), 3.49-3.55 (m, 1H), 3.75-3.86 (m, 2H), 3.96-4.01 (m,1H), 4.18-4.24 (m, 1H), 4.41-4.47 (m, 1H), 6.19 (s, 1H), 7.56 (dd,J=2.40, 8.80 Hz, 1H), 7.67 (d, J=7.20 Hz, 1H), 7.98 (d, J=8.80 Hz, 1H),8.48 (d, J=2.00 Hz, 1H), 8.62 (s, 1H), 9.09 (s, 1H). LC/MS: XBridge Phe8, □4.6×30 mm, 3.5 m; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; SolventB=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2min run time); retention time: 1.494 min; LCMS (ES-API), m/z 480.0(M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5 micron; Solvent A=5% ACN:95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 6.723 min; Purity: 97.5%.

Example 1635-(6-((4-Cyanophenyl)amino)-4-(isopropylamino)pyridin-3-yl)-N-(2-hydroxyethyl)-1,3,4-oxadiazole-2-carboxamide

¹H NMR: 400 MHz, CD₃OD: δ 1.37-1.39 (m, 6H), 3.50-3.60 (m, 1H),3.75-3.84 (m, 4H), 6.24 (s, 1H), 7.62-7.64 (m, 2H), 7.80-7.82 (m, 2H),7.92 (s, 1H), 8.70 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 m;Solvent A=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20mM NH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min run time);retention time: 1.58 min; LCMS (ES-API), m/z 406.2 (M−H). HPLC:Purospher RP18 (4.6×150 mm), 3 micron; Solvent A=20 mM NH₄COOAc;Solvent=ACN; Flow rate: 1.0 mL/min; Retention time: 8.905 min; Purity:95.7%.

Example 1645-(6-((4-Cyanophenyl)amino)-4-(isopropylamino)pyridin-3-yl)-N-(2-fluoro-3-hydroxypropyl)-1,3,4-oxadiazole-2-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.40 Hz, 6H), 3.50-3.68 (m, 4H),3.70-3.80 (m, 1H), 4.61-4.77 (m, 1H), 5.05 (t, J=5.60 Hz, 1H), 6.26 (s,1H), 7.49 (d, J=7.20 Hz, 1H), 7.69-7.71 (m, 2H), 7.86-7.89 (m, 2H), 8.66(s, 1H), 9.40 (t, J=6.00 Hz, 1H), 9.77 (s, 1H). LC/MS: ZORBAX SB C18,4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90%MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time);retention time: 1.389 min; LCMS (ES-API), m/z 440.2 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time:6.446 min; Purity: 95.2%.

Example 1654-((5-(5-(4-Aminopiperidine-1-carbonyl)-1,3,4-oxadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile

¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.40 Hz, 6H), 1.42-1.58 (m, 2H),1.97-2.04 (m, 2H), 3.01-3.07 (m, 1H), 3.31-3.38 (2H, merged with waterpeak), 3.74-3.82 (m, 1H), 4.42-4.52 (m, 2H), 6.28 (s, 1H), 7.05 (bs,2H), 7.54-7.56 (m, 1H), 7.69-7.71 (m, 2H), 7.87-7.89 (m, 2H), 8.52 (s,1H), 9.80 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10%MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient0-100% B over 2 min (3 min run time); retention time: 1.289 min; LCMS(ES-API), m/z 447.2 (M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μL/min; Retention time: 6.118 min; Purity: 99.2%.

Example 1665-(6-((4-Cyanophenyl)amino)-4-(isopropylamino)pyridin-3-yl)-N-(3-hydroxypropyl)-1,3,4-oxadiazole-2-carboxamide

¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.00 Hz, 6H), 1.69-1.76 (m, 2H),3.31-3.40 (2H, merged with water peak), 3.47-3.52 (m, 2H), 3.73-3.79 (m,1H), 4.53-4.55 (m, 1H), 6.26 (s, 1H), 7.50 (d, J=7.20 Hz, 1H), 7.69-7.71(m, 2H), 7.86-7.89 (m, 2H), 8.65 (s, 1H), 9.15-9.20 (m, 1H), 9.77 (s,1H). LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN:98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH;gradient 0-100% B over 1.5 min; retention time: 1.733 min; LCMS(ES-API), m/z 420.0 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.282 min; Purity: 97.2%.

Example 1675-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-N-methyl-1,3,4-oxadiazole-2-carboxamide

¹H NMR: 400 MHz, CD₃OD: δ 1.36 (d, J=6.40 Hz, 6H), 3.00 (s, 3H),3.79-3.87 (m, 1H), 6.19 (s, 1H), 7.56 (dd, J=2.40, 8.80 Hz, 1H),7.66-7.67 (m, 1H), 7.99 (d, J=8.80 Hz, 1H), 8.47 (d, J=2.40 Hz, 1H),8.65 (s, 1H), 9.09 (s, 1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 μm;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.515 min; LCMS (ES-API), m/z 410.2 (M+H). HPLC: Sunfire C18(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.921 min;Purity: 97.3%.

Example 1684-((5-(5-(4-Acetylpiperazine-1-carbonyl)-1,3,4-oxadiazol-2-yl)-4-(isopropylamino)pyridin-2-yl)amino)benzonitrile

Prepared following similar procedures as mentioned for the synthesis ofExample 157. ¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.40 Hz, 6H), 2.06(s, 3H), 3.59-3.81 (m, 7H), 3.94-4.02 (m, 2H), 6.28 (s, 1H), 7.55-7.57(m, 1H), 7.69-7.71 (m, 2H), 7.86-7.89 (m, 2H), 8.54 (s, 1H), 9.79 (s,1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 m; Solvent A=2% ACN: 98% H₂O:10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100%B over 1.5 min (3.2 min run time); retention time: 1.576 min; LCMS(ES-API), m/z 473.0 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.646 min; Purity: 97.9%.

Example 169N-(1-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carbonyl)piperidin-4-yl)acetamide

Prepared following similar procedures as mentioned for the synthesis ofExample 157. ¹H NMR: 400 MHz, CD₃OD: δ 1.37 (d, J=6.40 Hz, 6H),1.53-1.65 (m, 2H), 1.97 (s, 3H), 2.08-2.20 (m, 2H), 3.14-3.21 (m, 1H),3.48-3.54 (m, 1H), 3.82-3.86 (m, 1H), 4.04-4.05 (m, 1H), 4.56-4.59 (m,1H), 4.74-4.86 (1H, merged with CD₃OD peak), 6.19 (s, 1H), 7.57 (dd,J=2.40, 8.80 Hz, 1H), 7.99 (d, J=8.80 Hz, 1H), 8.48 (d, J=2.00 Hz, 1H),8.62 (s, 1H), 9.10 (s, 1H). LC/MS: XBridge Phe 8, □4.6×30 mm, 3.5 m;Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retentiontime: 1.487 min; LCMS (ES-API), m/z 521.0 (M+H). HPLC: XBridge Phenyl(150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5;Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 6.617 min;Purity: 91.6%.

Example 170N-(1-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carbonyl)piperidin-4-yl)methanesulfonamide

Prepared following similar procedures as mentioned for the synthesis ofExample 157. ¹H NMR: 400 MHz, DMSO-d₆: δ 1.32 (d, J=6.40 Hz, 6H),1.43-1.59 (m, 2H), 1.95-2.02 (m, 2H), 2.98 (s, 3H), 3.13-3.19 (m, 1H),3.42-3.56 (m, 2H), 3.74-3.82 (m, 1H), 4.29-4.33 (m, 1H), 4.40-4.43 (m,1H), 6.22 (s, 1H), 7.25 (d, J=7.20 Hz, 1H), 7.51 (d, J=6.80 Hz, 1H),7.62 (dd, J=2.00, 8.80 Hz, 1H), 7.98-8.00 (m, 1H), 8.53 (s, 1H), 8.66(d, J=2.00 Hz, 1H), 9.19 (s, 1H), 9.52 (s, 1H). LC/MS: XBridge Phe 8,□4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H₂O: 10 mM NH₄COOH; SolventB=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% B over 1.5 min (3.2min run time); retention time: 1.557 min; LCMS (ES-API), m/z 557.0(M+H). HPLC: XBridge Phenyl (150×4.6 mm), 3.5 micron; Solvent A=5% ACN:95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5;gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min;Retention time: 7.261 min; Purity: 98.07%.

Synthesis of ethyl2-(6-chloro-4-(isopropylamino)nicotinamido)-2-(hydroxyimino)acetate(69): A stirred solution of 6-chloro-4-(isopropylamino)nicotinic acid(2) in DCM (15 mL) was cooled to 0° C., oxalyl chloride (2 equiv) wasadded, followed by addition of 2 drops of DMF. The reaction mixture wasstirred at room temperature for 2 h. The reaction mixture wasconcentrated to remove excess of oxalyl chloride. The acyl chloride,generated in-situ was dissolved in DCM and added dropwise to a coolstirred solution of ethyl 2-amino oxamate (1.5 equiv.) and Et₃N (5equiv.) in DCM. The reaction temperature was slowly brought to roomtemperature and stirred for 2 h. The reaction mixture was diluted withDCM and washed with water, followed by brine solution. The DCM layer wascollected, dried over Na₂SO₄, filtered and concentrated. The crudematerial of ethyl2-(6-chloro-4-(isopropylamino)nicotinamido)-2-(hydroxyimino)acetateobtained was taken to next step as such without purification.

Synthesis of ethyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,2,4-oxadiazole-3-carboxylate(69): A solution of2-(6-chloro-4-(isopropylamino)nicotinamido)-2-(hydroxyimino)acetate (68)(800 mg) in DMF (15 mL) was heated at 150° C. for 3 h. The reactionmixture was concentrated. The crude material obtained was purified bycolumn chromatography through silica gel and MeOH: DCM to afford ethyl5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,2,4-oxadiazole-3-carboxylate.

Synthesis of5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,2,4-oxadiazole-3-carboxamide(70): Followed the same procedure as mentioned in the synthesis ofExample 87.

Example 171

Synthesis of5-(6-((4-cyanophenyl)amino)-4-(isopropylamino)pyridin-3-yl)-1,2,4-oxadiazole-3-carboxamide:A solution of5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,2,4-oxadiazole-3-carboxamide(70) (200 mg, 0.7 mmol) in NMP (2 mL) was treated with dioxan.HCl (4 mL)and heated in a closed condition at 150° C. for overnight. The reactionmixture was diluted with EtOAc and was quenched with ice cool water. TheEtOAc layer was then washed with sat.NaHCO₃ solution. The organic layerwas collected, dried over Na₂SO₄, filtered and concentrated. The crudematerial obtained was purified by prep HPLC to afford5-(6-((4-cyanophenyl)amino)-4-(isopropylamino)pyridin-3-yl)-1,2,4-oxadiazole-3-carboxamide.¹H NMR: 400 MHz, CD₃OD: δ 1.42 (d, J=6.80 Hz, 6H), 3.89-3.95 (m, 1H),6.33 (s, 1H), 7.64-7.66 (m, 2H), 7.76-7.78 (m, 2H), 8.71 (s, 1H). LC/MS:XBridge Phe 8, □4.6×30 mm, 3.5 m; Solvent A=2% ACN: 98% H₂O: 10 mMNH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min (3.2 min run time); retention time: 1.543 min; LCMS(ES-API), m/z 364.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μL/min; Retention time: 6.744 min; Purity: 98.4%.

Example 172

Synthesis of2-(6-(benzo[d]thiazol-6-ylamino)-4-(2,3-dihydroxypropylamino)pyridin-3-yl)-N-(2,3-dihydroxypropyl)thiazole-4-carboxamide:Example 172 was prepared in a similar fashion as Example 24 usingappropriate substitutions.

¹H NMR [ethyl2-(4-(allylamino)-6-chloropyridin-3-yl)thiazole-4-carboxylate (71)]: 400MHz, DMSO-d₆: δ 1.34 (t, J=7.20 Hz, 3H), 4.02-4.05 (m, 2H), 4.35 (q,J=6.80 Hz, 2H), 5.28 (dd, J=1.20, 10.60 Hz, 1H), 5.45 (dd, J=1.20, 17.40Hz, 1H), 5.98-6.07 (m, 1H), 6.86 (s, 1H), 8.61 (d, J=4.80 Hz, 1H),9.31-9.33 (m, 1H).

LC/MS [2-(4-(allylamino)-6-chloropyridin-3-yl)thiazole-4-carboxylic acid(72)]: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.72 min; LCMS (ES-API), m/z 296.3 (M+H).

LC/MS[N-allyl-2-(4-(allylamino)-6-chloropyridin-3-yl)thiazole-4-carboxamide(73)]: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.83 min; LCMS (ES-API), m/z 335.4 (M+H).

LC/MS[N-allyl-2-(4-(allylamino)-6-(benzo[d]thiazol-6-ylamino)pyridin-3-yl)thiazole-4-carboxamide(74)]: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA inwater; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min;retention time: 0.74 min; LCMS (ES-API), m/z 449.3 (M+H).

To a stirred solution ofN-allyl-2-(4-(allylamino)-6-(benzo[d]thiazol-6-ylamino)pyridin-3-yl)thiazole-4-carboxamide(74) (90 mg, 0.201 mmol) in mixed solvents acetone (7 mL) and water (2mL) was added Osmium Tetraoxide (6.37 mmol, 0.032 equiv.) at −78° C.After being stirred for 10 min, N-methyl morpholine oxide (NMO) (1.204mmol, 6 equiv.) was added to the reaction mixture in two portions at 30min interval. The reaction mixture was quenched with a pinch of NaHSO₃,and concentrated to give crude material. The crude material obtained waspurified by prep HPLC to furnish the title compound2-(6-(benzo[d]thiazol-6-ylamino)-4-((2,3-dihydroxypropyl)amino)pyridin-3-yl)-N-(2,3-dihydroxypropyl)thiazole-4-carboxamide.

¹H NMR: 400 MHz, DMSO-d₆: δ 3.25 (2H, merged with water peak), 3.85 (3H,merged with water peak), 3.44-3.53 (m, 3H), 3.66-3.68 (m, 1H), 3.89-3.92(m, 1H), 4.67 (s, 1H), 4.91-5.01 (m, 2H), 5.45 (s, 1H), 6.14 (s, 1H),7.59 (dd, J=2.00, 8.80 Hz, 1H), 7.96 (d, J=8.80 Hz, 1H), 8.09-8.16 (m,2H), 8.51 (s, 1H), 8.70 (d, J=2.40 Hz, 1H), 8.99-9.03 (m, 1H), 9.16 (s,1H), 9.37 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10%MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient0-100% B over 2 min (3 min run time); retention time: 1.205 min; LCMS(ES-API), m/z 517.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flowrate: 1.0 μL/min; Retention time: 8.085 min; Purity: 96.2%.

Synthesis of (6-chloro-4-(isopropylamino)pyridin-3-yl)methanol (75): Toa stirred solution of ethyl 6-chloro-4-(isopropylamino)nicotinate (2) (1g, 4.12 mmol) in dry DCM (30 mL), DIBAL-H (8.24 mmol, 2 equiv.) (1.0 Min DCM) was added dropwise at −78° C. The reaction mixture was stirredat −78° C. for 2 h, gradually, the reaction was allowed to warm up to−10° C. over 1 h. The reaction mixture was quenched with saturatedsolution of sodium potassium tarterate and allowed to stir at roomtemperature. The reaction mixture was filtered through a small pad ofcelite. The filtrate was washed with brine solution, dried over Na₂SO₄,filtered and concentrated to give crude alcohol. The crude materialobtained was purified by flash column chromatography through silica geland MeOH: CHCl₃ as eluent to afford(6-chloro-4-(isopropylamino)pyridin-3-yl)methanol. LC/MS: ZORBAX SB C18,4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90%MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time);retention time: 0.806 min; LCMS (ES-API), m/z 201.0 (M+H).

Synthesis of 6-chloro-4-(isopropylamino)nicotinaldehyde (76): To astirred solution of DMSO (13.43 mmol, 3.5 equiv.) in dry DCM (30 mL),oxalyl chloride (11.51 mmol, 3 equiv.) was added at −78° C. After beingstirred for 20 min, (6-chloro-4-(isopropylamino)pyridin-3-yl)methanol(75) (770 mg, 3.84 mmol) was added to the above reaction mixture at −78°C. and stirred for 2 h. The reaction mixture was allowed to warm up to−20° C. and added Et₃N (19.19 mmol, 5 equiv.) dropwise over a period of5 mins. The reaction mixture was allowed to warm up to 0° C. over 30mins and quenched with ice-flakes followed by 10% NaHCO₃ solution. Theorganic layer was separated, aqueous layer was extracted with DCM(twice). The organic layers were collected together, dried over Na₂SO₄,filtered and concentrated to give crude aldehyde. The crude materialobtained was purified by column chromatography through silica gel andEtOAc: pet ether as eluent provided the desired compound,6-chloro-4-(isopropylamino)nicotinaldehyde. LC/MS: Acquity BEH C182.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFAin ACN; gradient 0-100% B over 2 min; retention time: 0.76 min; LCMS(ES-API), m/z 199.26 (M+H).

Synthesis of 2-chloro-N-isopropyl-5-(oxazol-5-yl)pyridin-4-amine (77):To a stirred solution of 6-chloro-4-(isopropylamino)nicotinaldehyde (76)(200 mg, 1.007 mmol) in MeOH (10 mL) was added TOSMIC (1.208 mmol, 1.2equiv.) and K₂CO₃ (2.014 mmol, 2 equiv.) and refluxed for 4 h. Thereaction mixture was concentrated under reduced pressure. The residueobtained was dissolved in DCM and washed with water. The organic layerdried over Na₂SO₄, filtered and concentrated to give crude oxazolecompound. The crude material was purified by preparative TLC (elutedwith 40% EtOAC: pet ether) to afford2-chloro-N-isopropyl-5-(oxazol-5-yl)pyridin-4-amine. ¹H NMR: 400 MHz,DMSO-d₆: δ 1.19 (d, J=6.40 Hz, 6H), 3.80-3.85 (m, 1H), 5.98 (d, J=8.00Hz, 1H), 6.76 (s, 1H), 7.52 (s, 1H), 8.09 (s, 1H), 8.50 (s, 1H).

Example 173

Synthesis ofN2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(oxazol-5-yl)pyridine-2,4-diamine.Followed the procedure as mentioned in the synthesis of compound 3. ¹HNMR: 400 MHz, DMSO-d₆: δ 1.25 (d, J=6.40 Hz, 6H), 3.63-3.70 (m, 1H),5.39 (d, J=7.60 Hz, 1H), 6.16 (s, 1H), 7.36 (s, 1H), 7.58 (dd, J=2.40,8.80 Hz, 1H), 7.94 (d, J=8.80 Hz, 1H), 8.07 (s, 1H), 8.42 (s, 1H), 8.72(d, J=2.00 Hz, 1H), 9.14 (s, 1H), 9.23 (s, 1H) LC/MS: ZORBAX SB C18,4.6×50 mm, 5 □μm; Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90%MeOH: 10% H₂O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time);retention time: 1.379 min; LCMS (ES-API), m/z 352.0 (M+H). HPLC: SunfireC18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFApH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% Bover 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time:5.518 min; Purity: 99.4%.

Example 174(2S,3S)-3-((2-(Benzo[d]thiazol-6-ylamino)-5-(1H-1,2,4-triazol-5-yl)pyridin-4-yl)amino)-3-phenylpropane-1,2-diol

Step 1: A mixture of 4,6-dichloronicotinonitrile (760 mg, 4.39 mmol),(2S,3S)-3-amino-3-phenylpropane-1,2-diol (780 mg, 4.66 mmol) (Pico,Anna; Moyano, Albert ARKIVOC (Gainesville, Fla., United States) (2007),(4), 132-156) and DIPEA (921 μL, 5.27 mmol) in DMA (4393 μL) was stirredat 50° C. for 2.5 hours after which LCMS indicated ˜98% reactioncompletion. The vessel was cooled to room temperature and the darksolution was partitioned between ethyl acetate and water. The organicportion was washed with water and the combined aqueous layers wereextracted with ethyl acetate. The organics were combined, dried overanhydrous sodium sulfate, filtered and concentrated. The mixture wasdissolved in 2 mL of DCM and purified on a 40G ISCO column using 5-100%EA/Heptane. Following concentration, the regioisomers were collected asisolates 01 and 02.

Step 2: A mixture of6-chloro-4-((1S,2S)-2,3-dihydroxy-1-phenylpropylamino)nicotinonitrile(0.108 g, 0.356 mmol), benzo[d]thiazol-6-amine (0.187 g, 1.244 mmol) andNMP (1.422 mL) was stirred at 150° C. for 1 hour in a microwave reactor.The vessel was cooled to room temperature, diluted with water andfiltered. Following drying on a buchner funnel,6-(benzo[d]thiazol-6-ylamino)-4-((1S,2S)-2,3-dihydroxy-1-phenylpropylamino)nicotinonitrile(0.122 g, 0.292 mmol, 82% yield) was collected as a yellowish solid.LC-MS (m/z, M+1=418), Waters sunfire 4.6×50 mm C18 5 um 4 min/1 min holdtime 0-100% (A-B) A=10% MeOH-90% water-0.1% TFA, B=90% MeOH-10%water-0.1% TFA RT=2.06.

Step 3: In a tall reaction tube was added6-(benzo[d]thiazol-6-ylamino)-4-((1S,2S)-2,3-dihydroxy-1-phenylpropylamino)nicotinonitrile(0.075 g, 0.180 mmol), THF (0.898 mL) and hydrazine (1.692 mL, 53.9mmol). The reaction was heated to 95° C. for 16 hrs. The reaction wascooled and concentrated. MeOH (0.898 mL), formaldehyde (0.025 mL, 0.898mmol) and trimethyl orthoformate (0.099 mL, 0.898 mmol) were added andthe reaction stirred at rt overnight. The mixture was concentrated,dilute with DMF and filtered. Purification was done by HPLC using40-100% MeOH/Water/TFA over 10 minutes. Following concentration,collected(2S,3S)-3-(2-(benzo[d]thiazol-6-ylamino)-5-(1H-1,2,4-triazol-5-yl)pyridin-4-ylamino)-3-phenylpropane-1,2-diol,TFA (0.004 g, 6.63 μmol, 3.69% yield) as a white solid. LC-MS (m/z,M+1=460), Waters sunfire 4.6×50 mm C18 5 um 4 min/1 min hold time 0-100%(A-B) A=10% MeOH-90% water-0.1% TFA, B=90% MeOH-10% water-0.1% TFART=2.2. 1H NMR (400 MHz, METHANOL-D3) d 9.32 (s, 1H), 8.64 (s, 1H), 8.44(s, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.39-7.22 (m,7H), 5.98 (s, 1H), 4.75 (d, J=4.0 Hz, 1H), 4.11-4.04 (m, 1H), 3.50-3.42(m, 1H), 3.41-3.34 (m, 1H).

Example 1754-((5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)benzamide

Example 175 was prepared according to the general methods outlined inScheme 5. ¹H NMR: 400 MHz, DMSO-d₆: δ 1.29 (d, J=6.40 Hz, 6H), 3.71-3.76(m, 1H), 4.41 (s, 2H), 6.18 (s, 1H), 7.34 (s, 1H), 7.47-7.50 (m, 3H),7.58 (dd, J=2.00, 8.80 Hz, 1H), 7.87-7.89 (m, 2H), 7.95-7.97 (m, 2H),8.45 (s, 1H), 8.67 (d, J=2.00 Hz, 1H), 9.17 (s, 1H), 9.43 (s, 1H).LC/MS: Ascentis Express C18, 5×2.1 mm, 2.7 □μm; Solvent A=2% ACN: 98%H₂O: 10 mM NH₄COOH; Solvent B=98% ACN: 2% H₂O: 10 mM NH₄COOH; gradient0-100% B over 1.5 min; retention time: 1.78 min; LCMS (ES-API), m/z486.0 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5%ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFApH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate:1.0p/min; Retention time: 6.103 min; Purity: 97.6%.

Example 176N6′-(Benzo[d]thiazol-6-yl)-N4′-isopropyl-6-methoxy-[2,3′-bipyridine]-4′,6′-diamine

Step 1: 2-Chloro-5-iodo-N-isopropylpyridin-4-amine (0.25 g, 0.843 mmol),K₂CO₃ (0.350 g, 2.53 mmol), 6 methoxypyridine 2-boronic acid pinacolester (0.396 g, 1.68 mmol) and PdCl₂(dppf) (0.069 g, 0.084 mmol) weretaken in a sealed tube and dissolved in DMF (3 mL). The reaction masswas thoroughly purged with N2 and sealed. The reaction mass was heatedat 90° C. for 2 hours. The reaction was diluted with water, extractedwith ethyl acetate (3×20 mL) and dried. The combined organic layers wereconcentrated. The residue was combined with a previously performedexperiment and purified by column chromatography to obtain an off whitesolid (300 mg).

Step 2: 6′-Chloro-N-isopropyl-6-methoxy-[2,3′-bipyridin]-4′-amine (25mg, 0.090 mmol), 6-aminobenzothiazole (20.28 mg, 0.135 mmol), BINAP(1.121 mg, 1.800 mol), sodium tert-butoxide (26.0 mg, 0.270 mmol) weredissolved in Toluene (1 ml) in a sealed tube and thoroughly purged withN2 for 5 minutes. Pd₂(dba)₃ (3.3 mg, 3.6 μmol) was added and thereaction mass was once again purged with N2 for 5 minutes. The pressuretube was sealed and heated at 110° C. overnight. The reaction was cooledto rt and passed through a celite bed and washed with DCM. The filtratewas concentrated, dissolved in 10 mL water and extracted with DCM (3×8mL). The combined organic layers were dried, concentrated and purifiedvia preparative HPLC to afford Example 176. ¹H NMR: 400 MHz, CD₃OD: δ1.33 (d, J=6.40 Hz, 6H), 3.74-3.80 (m, 1H), 3.99 (s, 3H), 6.17 (s, 1H),6.71 (d, J=8.00 Hz, 1H), 7.34 (d, J=7.60 Hz, 1H), 7.52 (dd, J=2.40, 8.80Hz, 1H), 7.75 (t, J=8.00 Hz, 1H), 7.98 (d, J=8.80 Hz, 1H), 8.23 (s, 1H),8.34 (s, 1H), 9.07 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm;Solvent A=10% MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1%TFA; gradient 0-100% B over 2 min (3 min run time); retention time:1.713 min; LCMS (ES-API), m/z 392.2 (M+H). HPLC: Sunfire C18 (150×4.6mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; SolventB=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23min run time); Flow rate: 1.0 μl/min; Retention time: 7.274 min; Purity:98.1%.

Example 177N2-(Benzo[d]thiazol-6-yl)-5-(1H-indazol-6-yl)-N4-isopropylpyridine-2,4-diamine

Step 1: 2-Chloro-5-iodo-N-isopropylpyridin-4-amine (0.15 g, 0.506 mmol)in Acetonitrile (2 mL) was added Na₂CO₃ (0.161 g, 1.518 mmol) followedby 1H-indazole-5-boronic acid pinacol ester (0.124 g, 0.508 mmol) andtetrakistriphenyl phosphine Pd(0) (0.026 g, 0.023 mmol). The reactionwas thoroughly degassed and subjected to microwave radiation at 110 Cfor 2 hours. The reaction mixture was concentrated to removeacetonitrile, added water (10 mL) and extracted with ethyl acetate (3times×10 mL). The combined extracts were dried purified via columnchromatography. The reaction was performed 3 times to provide of 30 mgwhich was used directly in the next step.

Step 2: 2-Chloro-5-(1H-indazol-5-yl)-N-isopropylpyridin-4-amine (30 mg,0.105 mmol) in Dioxane (1 ml) in a microwave vial was added Xantphos(48.4 mg, 0.084 mmol), cesium carbonate (102 mg, 0.314 mmol),6-aminobenzothiazole (18.8 mg, 0.126 mmol) and Pd₂(dba)₃ (38.3 mg, 0.042mmol) and purged with N2 thoroughly for 10 minutes. The reaction masswas subjected to microwave radiation for 3 hours at 150° C. The crudemass was passed through a celite bed and the filtrate was concentratedto remove dioxane then added 10 mL of water and extracted with DCM (3times×8 mL). The combined organic layers were dried and concentrated.The crude mass was purified by prep TLC first and then preparative HPLCto give Example 177. ¹H NMR: 400 MHz, CD₃OD: δ 1.20 (d, J=6.40 Hz, 6H),3.70-3.73 (m, 1H), 6.20 (s, 1H), 7.41 (dd, J=1.60, 8.80 Hz, 1H), 7.52(dd, J=2.40, 8.80 Hz, 1H), 7.67-7.69 (m, 2H), 7.79 (dd, J=0.80, 1.20 Hz,1H), 7.98 (d, J=9.20 Hz, 1H), 8.13 (s, 1H), 8.33 (d, J=2.00 Hz, 1H),9.07 (s, 1H). LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 □μm; Solvent A=10%MeOH: 90% H₂O: 0.1% TFA; Solvent B=90% MeOH: 10% H₂O: 0.1% TFA; gradient0-100% B over 2 min (3 min run time); retention time: 1.482 min; LCMS(ES-API), m/z 401.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 l/min; Retention time: 6.211 min; Purity: 99.3%.

Example 1783-((5-(4-(Isopropylamino)-6-(quinoxalin-6-ylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)propan-1-ol

Example 178 was prepared according to the general methods outlined inScheme 5. ¹H NMR: 400 MHz, DMSO-d₆: δ 1.31 (d, J=6.40 Hz, 6H), 1.73-1.76(m, 2H), 3.33 (2H, merged with water peak), 3.48-3.52 (m, 2H), 3.74-3.75(m, 1H), 4.49-4.51 (m, 1H), 6.27 (s, 1H), 7.59 (d, J=7.20 Hz, 1H), 7.77(t, J=5.60 Hz, 1H), 7.90-7.97 (m, 2H), 8.37 (s, 1H), 8.68-8.69 (m, 2H),8.79 (d, J=2.00 Hz, 1H), 9.66 (s, 1H). LC/MS: Purospher@star RP-18, 4×55mm, 3 m; Solvent A=10% ACN: 90% H₂O: 20 mM NH₄OAc; Solvent B=90% ACN:10% H₂O: 20 mM NH₄COOAc; gradient 0-100% B over 1.5 min (3.2 min runtime); retention time: 1.374 min; LCMS (ES-API), m/z 421.2 (M+H). HPLC:XBridge Phenyl (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H₂O:0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient0-100% B over 30 min (36 min run time); Flow rate: 1.0 μl/min; Retentiontime: 10.606 min; Purity: 97.8%.

Example 179

Example 179 was prepared according to the general methods outlined inScheme 5. ¹H NMR: 400 MHz, DMSO-d₆: δ 1.31 (d, J=6.40 Hz, 6H), 1.74-1.77(m, 2H), 3.32 (2H, merged with water peak), 3.52-3.53 (m, 2H), 3.72-3.77(m, 1H), 4.50-4.53 (m, 1H), 6.25 (s, 1H), 7.57 (d, J=7.20 Hz, 1H), 7.75(t, J=5.60 Hz, 1H), 7.92 (d, J=9.20 Hz, 1H), 8.04-8.07 (m, 1H), 8.37 (s,1H), 8.66 (d, J=2.40 Hz, 1H), 9.09 (s, 1H), 9.44 (s, 1H), 9.63 (s, 1H).LC/MS: Purospher@star RP-18, 4×55 mm, 3 m; Solvent A=10% ACN: 90% H₂O:20 mM NH₄OAc; Solvent B=90% ACN: 10% H₂O: 20 mM NH₄COOAc; gradient0-100% B over 1.5 min (3.2 min run time); retention time: 1.337 min;LCMS (ES-API), m/z 419.2 (M−H). HPLC: Eclipse XDB C18 (150×4.6 mm) 5micron; Solvent A=20 mM NH₄OAc in water; Solvent B=ACN; gradient 0-100%B over 23 min; Flow rate=1.0 ml/min; Retention time: 14.52 min; Purity:95.4%.

The compounds shown in Table 13 were prepared according to the generalmethods used for the preparation of Example 2, appropriatelysubstituting reagents as needed to provide the examples below.

TABLE 13

Ex- ample No. R₁ R₂ 180

181

182

Example 180(3-Hydroxypyrrolidin-1-yl)(5-(4-(isopropylamino)-6-(quinoxalin-6-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanone,20 mg

LC/MS: m/z 477.2 (M+H); HPLC: Eclipse XDB C18 (150×4.6 mm) 5 micron;Solvent A=20 mM NH₄OAc in water; Solvent B=ACN; gradient 0-100% B over23 min; Flow rate=1.0 ml/min; Retention time: 14.52 min; Purity: 97%.

Example 181(R)-(3-Hydroxypyrrolidin-1-yl)(5-(4-(isopropylamino)-6-(pyrazolo[1,5-a]pyridin-5-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanone,20 mg

LC/MS: m/z 465.2 (M+H); HPLC: HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μl/min; Retention time: 5.30 min; Purity: 99.8%.

Example 182(R)-(3-Hydroxypyrrolidin-1-yl)(5-(6-(imidazo[1,2-b]pyridazin-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanone,20 mg

LC/MS: m/z 466.2 (M+H); HPLC: HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μl/min; Retention time: 7.77 min; Purity: 99.3%.

Additional compounds (Examples 183-186) were prepared according to themethods outlined for Example 2.

Example 183(5-(4-(Cyclobutylamino)-6-(quinoxalin-6-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone,25 mg

LC/MS: m/z 489.2 (M+H); HPLC: HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min runtime); Flow rate: 1.0 μl/min; Retention time: 5.74 min; Purity: 95.9%.

Example 184(5-(4-(Cyclopropylamino)-6-(quinolin-6-ylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone

LC/MS: m/z 473.9 (M+H); HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron;Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H₂O:0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flowrate: 1.0 μl/min; Retention time: 8.95 min; Purity: 99.1%.

Example 185(5-(6-(Benzo[d]thiazol-6-ylamino)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone,8 mg

LC/MS: m/z 524.0 (M+H); HPLC: Eclipse XDB C18 (150×4.6 mm) 5 micron;Solvent A=20 mM NH₄OAc in water; Solvent B=ACN; gradient 0-100% B over23 min; Flow rate=1.0 ml/min; Retention time: 7.63 min; Purity: 94.3%.

Example 186(5-(4-((2-Fluorocyclopentyl)amino)-6-(quinoxalin-6-ylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone,1.5 mg

LC/MS: m/z 519.2 (M+H); HPLC: Xbridge Phenyl C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 12 min (15 min runtime); Flow rate: 1.0 μl/min; Retention time: 6.63 min; Purity: 94.6%.

Example 187

Prepared according to the method outlined for Example 21 and 22.2-(4-(isopropylamino)-6-(quinoxalin-6-ylamino)pyridin-3-yl)-N,5-dimethylthiazole-4-carboxamide,35 mg. LC/MS: m/z 434.5 (M+H); HPLC: Xbridge Phenyl C18 (150×4.6 mm),3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95%ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 12 min (15 min runtime); Flow rate: 1.0 μl/min; Retention time: 6.56 min; Purity: 96.8%.

Example 188

Prepared according to the method outlined for Example 21 and 22.2-(4-(isopropylamino)-6-(quinazolin-6-ylamino)pyridin-3-yl)-N,5-dimethylthiazole-4-carboxamide,25 mg. LC/MS: m/z 434.2 (M+H); HPLC: Xbridge Phenyl C18 (150×4.6 mm),3.5 micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95%ACN: 5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 12 min (20 min runtime); Flow rate: 1.0 μl/min; Retention time: 12.97 min; Purity: 91.2%.

Example 189

Prepared according to the methods outlined for Examples 111 and 1343-((5-(4-(cyclopropylamino)-6-(quinolin-6-ylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)propan-1-ol,5 mg. LC/MS: m/z 417.8 (M+H); HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 18 min (23 min runtime); Flow rate: 1.0 μl/min; Retention time: 7.51 min; Purity: 96.6%.

Example 190

Prepared according to the methods outlined for Examples 111 and 134.3-((5-(4-(cyclopropylamino)-6-(quinoxalin-6-ylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)propan-1-ol,6 mg. LC/MS: m/z 418.8 (M+H); HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 18 min (23 min runtime); Flow rate: 1.0 μl/min; Retention time: 9.02 min; Purity: 98.1%.

Example 191

Prepared according to the methods outlined for Examples 111 and 134.3-((5-(6-(benzo[d]thiazol-6-ylamino)-4-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)propan-1-ol,10 mg. LC/MS: m/z 468.2 (M+H); HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 12 min (15 min runtime); Flow rate: 1.0 μl/min; Retention time: 5.14 min; Purity: 97.3%.

Example 192

Prepared according to the methods outlined for Examples 111 and 134.3-((5-(6-(benzo[d]thiazol-6-ylamino)-4-((2-fluorocyclopentyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)propan-1-ol,8 mg. LC/MS: m/z 470.2 (M+H); HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 12 min (15 min runtime); Flow rate: 1.0 μl/min; Retention time: 5.98 min; Purity: 93.5%.

Example 193

Prepared according to the methods outlined for Examples 111 and 134.3-((5-(6-(benzo[c][1,2,5]oxadiazol-5-ylamino)-4-((2-fluorocyclopentyl)amino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)propan-1-ol,26 mg. LC/MS: m/z 453.2 (M−H); HPLC: Sunfire C18 (150×4.6 mm), 3.5micron; Solvent A=5% ACN: 95% H₂O: 0.05% TFA pH=2.5; Solvent B=95% ACN:5% H₂O: 0.05% TFA pH=2.5; gradient 0-100% B over 12 min (15 min runtime); Flow rate: 1.0 μl/min; Retention time: 6.85 min; Purity: 96.6%.

1-15. (canceled)
 16. A compound having the following formula:

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein Xis N; R is —C(═O)—R¹, —C(═O)O—R¹ or —C(═O)NR¹¹—R¹; R¹ is pyrrolidinylsubstituted with 0-3 R^(1a); R^(1a) is hydrogen, —OCF₃, —CN,—(CH₂)_(r)OR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)₂R^(c), or C₁₋₆ alkyl substituted with 0-2R^(a); R² is benzo[d]thiazolyl; R³ is propyl substituted with 0-3R^(3a); R^(3a) is —OH or phenyl; R¹¹ at each occurrence is hydrogen;R^(a) is R^(d), F, Cl, Br, —OCF₃, —CF₃, —CHF₂, or —CN; R^(b) is R^(e),C₁₋₆ alkyl, or C₁₋₆ haloalkyl; R^(c) is —CH₃; R^(d) is hydrogen; R^(e)is hydrogen; p is 0, 1, or 2; and r is 0, 1, or
 2. 17. The compoundaccording to claim 16 or a stereoisomer or pharmaceutically-acceptablesalt thereof, wherein R² is:


18. The compound according to claim 16, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein R³ is —CH(CH₃)₂. 19.The compound according to claim 16, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein R¹ is pyrrolidinylsubstituted with 0-2 R^(1a).
 20. The compound according to claim 16, ora stereoisomer or pharmaceutically-acceptable salt thereof, wherein R¹is pyrrolidinyl substituted with 0-1 R^(1a).
 21. The compound accordingto claim 16, or a stereoisomer or pharmaceutically-acceptable saltthereof, wherein R^(1a) is H, —OH, —CH₂OH, —NH₂, —NHC(O)CH₃, or—NHS(O)₂CH₃.
 22. The compound according to claim 16, or a stereoisomeror pharmaceutically-acceptable salt thereof, wherein R¹ is C₁₋₆ alkylsubstituted with 0-4 R^(1a) or C₂₋₆ alkynyl substituted with 0-3 R^(1a).23. The compound according to claim 16, or a stereoisomer orpharmaceutically-acceptable salt thereof, wherein said compound isselected from(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone(2);(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone(5);(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone(6);(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)(3-hydroxypyrrolidin-1-yl)methanone(7);N-(1-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3-yl)acetamide(8);(3-Aminopyrrolidin-1-yl)(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanone(12);N-(1-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3-yl)acetamide(13);(3-Aminopyrrolidin-1-yl)(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanone(14); andN-(1-(5-(6-(Benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazole-2-carbonyl)pyrrolidin-3-yl)methanesulfonamide(15).
 24. A pharmaceutical composition comprising one or more compoundsaccording to claim 16 and a pharmaceutically acceptable carrier ordiluent.
 25. A method of treating a disease, comprising administering toa patient a therapeutically-effective amount of a compound according toclaim 16, wherein the disease is an inflammatory or autoimmune disease.26. The method of claim 25 wherein the disease is selected from Crohn's,disease, ulcerative colitis, asthma, graft versus host disease,allograft rejection, chronic obstructive pulmonary disease, Graves'disease, rheumatoid arthritis, systemic lupus erythematosis, psoriasis,adult onset stills, systemic onset juvenile idiopathic arthritis,multiple sclerosis, neuropathic pain, gout, and gouty arthritis.